Archive for May, 2020

Los Angeles, United State: Complete study of the global Milk Thistle Health Tonic market is carried out by the analysts in this report, taking into consideration key factors like drivers, challenges, recent trends, opportunities, advancements, and competitive landscape. This report offers a clear understanding of the present as well as future scenario of the global Milk Thistle Health Tonic industry. Research techniques like PESTLE and Porters Five Forces analysis have been deployed by the researchers. They have also provided accurate data on Milk Thistle Health Tonic production, capacity, price, cost, margin, and revenue to help the players gain a clear understanding into the overall existing and future market situation.

The research study includes great insights about critical market dynamics, including drivers, restraints, trends, and opportunities. It also includes various types of market analysis such as competitive analysis, manufacturing cost analysis, manufacturing process analysis, price analysis, and analysis of market influence factors. It is a complete study on the global Milk Thistle Health Tonic market that can be used as a set of effective guidelines for ensuring strong growth in the coming years. It caters to all types of interested parties, viz. stakeholders, market participants, investors, market researchers, and other individuals associated with the Milk Thistle Health Tonic business.

Get Full PDF Sample Copy of Report: (Including Full TOC, List of Tables & Figures, Chart)https://www.qyresearch.com/sample-form/form/1703248/global-milk-thistle-health-tonic-market

It is important for every market participant to be familiar with the competitive scenario in the global Milk Thistle Health Tonic industry. In order to fulfil the requirements, the industry analysts have evaluated the strategic activities of the competitors to help the key players strengthen their foothold in the market and increase their competitiveness.

Key Players Mentioned in the Global Milk Thistle Health Tonic Market Research Report: , Health Genesis, Pure Encapsulations, Regis, Solgar, Aksuvital, BEC, NC, Life Extension, Swisse, HerbsofGold

Global Milk Thistle Health Tonic Market Segmentation by Product:, Tablets, Capsules, Others

Global Milk Thistle Health Tonic Market Segmentation by Application: Dietary Supplement, Health Food Health Genesis, Pure Encapsulations, Regis, Solgar, Aksuvital, BEC, NC, Life Extension, Swisse, HerbsofGold

The report has classified the global Milk Thistle Health Tonic industry into segments including product type and application. Every segment is evaluated based on growth rate and share. Besides, the analysts have studied the potential regions that may prove rewarding for the Milk Thistle Health Tonic manufcaturers in the coming years. The regional analysis includes reliable predictions on value and volume, thereby helping market players to gain deep insights into the overall Milk Thistle Health Tonic industry.

Additionally, the industry analysts have studied key regions including North America, Europe, Asia Pacific, Latin America, and Middle East and Africa, along with their respective countries. Here, they have given a clear-cut understanding of the present and future situations of the global Milk Thistle Health Tonic industry in key regions. This will help the key players to focus on the lucrative regional markets.

Key questions answered in the report:

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Table od Content

1 Milk Thistle Health Tonic Market Overview1.1 Milk Thistle Health Tonic Product Overview1.2 Milk Thistle Health Tonic Market Segment by Type1.2.1 Tablets1.2.2 Capsules1.2.3 Others1.3 Global Milk Thistle Health Tonic Market Size by Type (2015-2026)1.3.1 Global Milk Thistle Health Tonic Market Size Overview by Type (2015-2026)1.3.2 Global Milk Thistle Health Tonic Historic Market Size Review by Type (2015-2020)1.3.2.1 Global Milk Thistle Health Tonic Sales Market Share Breakdown by Type (2015-2026)1.3.2.2 Global Milk Thistle Health Tonic Revenue Market Share Breakdown by Type (2015-2026)1.3.2.3 Global Milk Thistle Health Tonic Average Selling Price (ASP) by Type (2015-2026)1.3.3 Global Milk Thistle Health Tonic Market Size Forecast by Type (2021-2026)1.3.3.1 Global Milk Thistle Health Tonic Sales Market Share Breakdown by Application (2021-2026)1.3.3.2 Global Milk Thistle Health Tonic Revenue Market Share Breakdown by Application (2021-2026)1.3.3.3 Global Milk Thistle Health Tonic Average Selling Price (ASP) by Application (2021-2026)1.4 Key Regions Market Size Segment by Type (2015-2020)1.4.1 North America Milk Thistle Health Tonic Sales Breakdown by Type (2015-2026)1.4.2 Europe Milk Thistle Health Tonic Sales Breakdown by Type (2015-2026)1.4.3 Asia-Pacific Milk Thistle Health Tonic Sales Breakdown by Type (2015-2026)1.4.4 Latin America Milk Thistle Health Tonic Sales Breakdown by Type (2015-2026)1.4.5 Middle East and Africa Milk Thistle Health Tonic Sales Breakdown by Type (2015-2026)1.5 Coronavirus Disease 2019 (Covid-19): Milk Thistle Health Tonic Industry Impact1.5.1 How the Covid-19 is Affecting the Milk Thistle Health Tonic Industry1.5.1.1 Milk Thistle Health Tonic Business Impact Assessment Covid-191.5.1.2 Supply Chain Challenges1.5.1.3 COVID-19s Impact On Crude Oil and Refined Products1.5.2 Market Trends and Milk Thistle Health Tonic Potential Opportunities in the COVID-19 Landscape1.5.3 Measures / Proposal against Covid-191.5.3.1 Government Measures to Combat Covid-19 Impact1.5.3.2 Proposal for Milk Thistle Health Tonic Players to Combat Covid-19 Impact 2 Global Milk Thistle Health Tonic Market Competition by Company2.1 Global Top Players by Milk Thistle Health Tonic Sales (2015-2020)2.2 Global Top Players by Milk Thistle Health Tonic Revenue (2015-2020)2.3 Global Top Players Milk Thistle Health Tonic Average Selling Price (ASP) (2015-2020)2.4 Global Top Manufacturers Milk Thistle Health Tonic Manufacturing Base Distribution, Sales Area, Product Type2.5 Milk Thistle Health Tonic Market Competitive Situation and Trends2.5.1 Milk Thistle Health Tonic Market Concentration Rate (2015-2020)2.5.2 Global 5 and 10 Largest Manufacturers by Milk Thistle Health Tonic Sales and Revenue in 20192.6 Global Top Manufacturers by Company Type (Tier 1, Tier 2 and Tier 3) (based on the Revenue in Milk Thistle Health Tonic as of 2019)2.7 Date of Key Manufacturers Enter into Milk Thistle Health Tonic Market2.8 Key Manufacturers Milk Thistle Health Tonic Product Offered2.9 Mergers & Acquisitions, Expansion 3 Global Milk Thistle Health Tonic Status and Outlook by Region (2015-2026)3.1 Global Milk Thistle Health Tonic Market Size and CAGR by Region: 2015 VS 2020 VS 20263.2 Global Milk Thistle Health Tonic Market Size Market Share by Region (2015-2020)3.2.1 Global Milk Thistle Health Tonic Sales Market Share by Region (2015-2020)3.2.2 Global Milk Thistle Health Tonic Revenue Market Share by Region (2015-2020)3.2.3 Global Milk Thistle Health Tonic Sales, Revenue, Price and Gross Margin (2015-2020)3.3 Global Milk Thistle Health Tonic Market Size Market Share by Region (2021-2026)3.3.1 Global Milk Thistle Health Tonic Sales Market Share by Region (2021-2026)3.3.2 Global Milk Thistle Health Tonic Revenue Market Share by Region (2021-2026)3.3.3 Global Milk Thistle Health Tonic Sales, Revenue, Price and Gross Margin (2021-2026)3.4 North America Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)3.4.1 North America Milk Thistle Health Tonic Revenue YoY Growth (2015-2026)3.4.2 North America Milk Thistle Health Tonic Sales YoY Growth (2015-2026)3.5 Asia-Pacific Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)3.5.1 Asia-Pacific Milk Thistle Health Tonic Revenue YoY Growth (2015-2026)3.5.2 Asia-Pacific Milk Thistle Health Tonic Sales YoY Growth (2015-2026)3.6 Europe Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)3.6.1 Europe Milk Thistle Health Tonic Revenue YoY Growth (2015-2026)3.6.2 Europe Milk Thistle Health Tonic Sales YoY Growth (2015-2026)3.7 Latin America Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)3.7.1 Latin America Milk Thistle Health Tonic Revenue YoY Growth (2015-2026)3.7.2 Latin America Milk Thistle Health Tonic Sales YoY Growth (2015-2026)3.8 Middle East and Africa Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)3.8.1 Middle East and Africa Milk Thistle Health Tonic Revenue YoY Growth (2015-2026)3.8.2 Middle East and Africa Milk Thistle Health Tonic Sales YoY Growth (2015-2026) 4 Global Milk Thistle Health Tonic by Application4.1 Milk Thistle Health Tonic Segment by Application4.1.1 Dietary Supplement4.1.2 Health Food4.2 Global Milk Thistle Health Tonic Sales by Application: 2015 VS 2020 VS 20264.3 Global Milk Thistle Health Tonic Historic Sales by Application (2015-2020)4.4 Global Milk Thistle Health Tonic Forecasted Sales by Application (2021-2026)4.5 Key Regions Milk Thistle Health Tonic Market Size by Application4.5.1 North America Milk Thistle Health Tonic by Application4.5.2 Europe Milk Thistle Health Tonic by Application4.5.3 Asia-Pacific Milk Thistle Health Tonic by Application4.5.4 Latin America Milk Thistle Health Tonic by Application4.5.5 Middle East and Africa Milk Thistle Health Tonic by Application 5 North America Milk Thistle Health Tonic Market Size by Country (2015-2026)5.1 North America Market Size Market Share by Country (2015-2020)5.1.1 North America Milk Thistle Health Tonic Sales Market Share by Country (2015-2020)5.1.2 North America Milk Thistle Health Tonic Revenue Market Share by Country (2015-2020)5.2 North America Market Size Market Share by Country (2021-2026)5.2.1 North America Milk Thistle Health Tonic Sales Market Share by Country (2021-2026)5.2.2 North America Milk Thistle Health Tonic Revenue Market Share by Country (2021-2026)5.3 North America Market Size YoY Growth by Country5.3.1 U.S. Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)5.3.2 Canada Milk Thistle Health Tonic Market Size YoY Growth (2015-2026) 6 Europe Milk Thistle Health Tonic Market Size by Country (2015-2026)6.1 Europe Market Size Market Share by Country (2015-2020)6.1.1 Europe Milk Thistle Health Tonic Sales Market Share by Country (2015-2020)6.1.2 Europe Milk Thistle Health Tonic Revenue Market Share by Country (2015-2020)6.2 Europe Market Size Market Share by Country (2021-2026)6.2.1 Europe Milk Thistle Health Tonic Sales Market Share by Country (2021-2026)6.2.2 Europe Milk Thistle Health Tonic Revenue Market Share by Country (2021-2026)6.3 Europe Market Size YoY Growth by Country6.3.1 Germany Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)6.3.2 France Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)6.3.3 U.K. Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)6.3.4 Italy Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)6.3.5 Russia Milk Thistle Health Tonic Market Size YoY Growth (2015-2026) 7 Asia-Pacific Milk Thistle Health Tonic Market Size by Country (2015-2026)7.1 Asia-Pacific Market Size Market Share by Country (2015-2020)7.1.1 Asia-Pacific Milk Thistle Health Tonic Sales Market Share by Country (2015-2020)7.1.2 Asia-Pacific Milk Thistle Health Tonic Revenue Market Share by Country (2015-2020)7.2 Asia-Pacific Market Size Market Share by Country (2021-2026)7.2.1 Asia-Pacific Milk Thistle Health Tonic Sales Market Share by Country (2021-2026)7.2.2 Asia-Pacific Milk Thistle Health Tonic Revenue Market Share by Country (2021-2026)7.3 Asia-Pacific Market Size YoY Growth by Country7.3.1 China Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.2 Japan Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.3 South Korea Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.4 India Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.5 Australia Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.6 Taiwan Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.7 Indonesia Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.8 Thailand Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.9 Malaysia Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.10 Philippines Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)7.3.11 Vietnam Milk Thistle Health Tonic Market Size YoY Growth (2015-2026) 8 Latin America Milk Thistle Health Tonic Market Size by Country (2015-2026)8.1 Latin America Market Size Market Share by Country (2015-2020)8.1.1 Latin America Milk Thistle Health Tonic Sales Market Share by Country (2015-2020)8.1.2 Latin America Milk Thistle Health Tonic Revenue Market Share by Country (2015-2020)8.2 Latin America Market Size Market Share by Country (2021-2026)8.2.1 Latin America Milk Thistle Health Tonic Sales Market Share by Country (2021-2026)8.2.2 Latin America Milk Thistle Health Tonic Revenue Market Share by Country (2021-2026)8.3 Latin America Market Size YoY Growth by Country8.3.1 Mexico Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)8.3.2 Brazil Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)8.3.3 Argentina Milk Thistle Health Tonic Market Size YoY Growth (2015-2026) 9 Middle East and Africa Milk Thistle Health Tonic Market Size by Country (2015-2026)9.1 Middle East and Africa Market Size Market Share by Country (2015-2020)9.1.1 Middle East and Africa Milk Thistle Health Tonic Sales Market Share by Country (2015-2020)9.1.2 Middle East and Africa Milk Thistle Health Tonic Revenue Market Share by Country (2015-2020)9.2 Middle East and Africa Market Size Market Share by Country (2021-2026)9.2.1 Middle East and Africa Milk Thistle Health Tonic Sales Market Share by Country (2021-2026)9.2.2 Middle East and Africa Milk Thistle Health Tonic Revenue Market Share by Country (2021-2026)9.3 Middle East and Africa Market Size YoY Growth by Country9.3.1 Turkey Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)9.3.2 Saudi Arabia Milk Thistle Health Tonic Market Size YoY Growth (2015-2026)9.3.3 U.A.E Milk Thistle Health Tonic Market Size YoY Growth (2015-2026) 10 Company Profiles and Key Figures in Milk Thistle Health Tonic Business10.1 Health Genesis10.1.1 Health Genesis Corporation Information10.1.2 Health Genesis Description, Business Overview and Total Revenue10.1.3 Health Genesis Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.1.4 Health Genesis Milk Thistle Health Tonic Products Offered10.1.5 Health Genesis Recent Development10.2 Pure Encapsulations10.2.1 Pure Encapsulations Corporation Information10.2.2 Pure Encapsulations Description, Business Overview and Total Revenue10.2.3 Pure Encapsulations Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.2.4 Health Genesis Milk Thistle Health Tonic Products Offered10.2.5 Pure Encapsulations Recent Development10.3 Regis10.3.1 Regis Corporation Information10.3.2 Regis Description, Business Overview and Total Revenue10.3.3 Regis Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.3.4 Regis Milk Thistle Health Tonic Products Offered10.3.5 Regis Recent Development10.4 Solgar10.4.1 Solgar Corporation Information10.4.2 Solgar Description, Business Overview and Total Revenue10.4.3 Solgar Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.4.4 Solgar Milk Thistle Health Tonic Products Offered10.4.5 Solgar Recent Development10.5 Aksuvital10.5.1 Aksuvital Corporation Information10.5.2 Aksuvital Description, Business Overview and Total Revenue10.5.3 Aksuvital Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.5.4 Aksuvital Milk Thistle Health Tonic Products Offered10.5.5 Aksuvital Recent Development10.6 BEC10.6.1 BEC Corporation Information10.6.2 BEC Description, Business Overview and Total Revenue10.6.3 BEC Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.6.4 BEC Milk Thistle Health Tonic Products Offered10.6.5 BEC Recent Development10.7 NC10.7.1 NC Corporation Information10.7.2 NC Description, Business Overview and Total Revenue10.7.3 NC Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.7.4 NC Milk Thistle Health Tonic Products Offered10.7.5 NC Recent Development10.8 Life Extension10.8.1 Life Extension Corporation Information10.8.2 Life Extension Description, Business Overview and Total Revenue10.8.3 Life Extension Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.8.4 Life Extension Milk Thistle Health Tonic Products Offered10.8.5 Life Extension Recent Development10.9 Swisse10.9.1 Swisse Corporation Information10.9.2 Swisse Description, Business Overview and Total Revenue10.9.3 Swisse Milk Thistle Health Tonic Sales, Revenue and Gross Margin (2015-2020)10.9.4 Swisse Milk Thistle Health Tonic Products Offered10.9.5 Swisse Recent Development10.10 HerbsofGold10.10.1 Company Basic Information, Manufacturing Base and Competitors10.10.2 Milk Thistle Health Tonic Product Category, Application and Specification10.10.3 HerbsofGold Milk Thistle Health Tonic Sales, Revenue, Price and Gross Margin (2015-2020)10.10.4 Main Business Overview10.10.5 HerbsofGold Recent Development 11 Milk Thistle Health Tonic Upstream, Opportunities, Challenges, Risks and Influences Factors Analysis11.1 Milk Thistle Health Tonic Key Raw Materials11.1.1 Key Raw Materials11.1.2 Key Raw Materials Price11.1.3 Raw Materials Key Suppliers11.2 Manufacturing Cost Structure11.2.1 Raw Materials11.2.2 Labor Cost11.2.3 Manufacturing Expenses11.3 Milk Thistle Health Tonic Industrial Chain Analysis11.4 Market Opportunities, Challenges, Risks and Influences Factors Analysis11.4.1 Market Opportunities and Drivers11.4.2 Market Challenges11.4.3 Market Risks11.4.4 Porters Five Forces Analysis 12 Market Strategy Analysis, Distributors12.1 Sales Channel12.2 Distributors12.3 Downstream Customers 13 Research Findings and Conclusion 14 Appendix14.1 Methodology/Research Approach14.1.1 Research Programs/Design14.1.2 Market Size Estimation14.1.3 Market Breakdown and Data Triangulation14.2 Data Source14.2.1 Secondary Sources14.2.2 Primary Sources14.3 Author Details14.4 Disclaimer

About Us:

QY Research established in 2007, focus on custom research, management consulting, IPO consulting, industry chain research, data base and seminar services. The company owned a large basic data base (such as National Bureau of statistics database, Customs import and export database, Industry Association Database etc), experts resources (included energy automotive chemical medical ICT consumer goods etc.

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Milk Thistle Health Tonic Market In Depth Research with Industry Driving Factors, Consumer Behaviour Analysis, Future Trends, Key Players and Forecast...

When it comes to our skin care goals, one key benefit seems to rule them all anti-aging. While aging skin may be inevitable, taking preventative action now can reduce the visible signs of aging long-term. Two key elements in this process are supporting collagen production and exfoliation. In other words, boosting the components of skin that keep it looking plump, while ridding the skins surface of older cells that can tend to build up over time.

In our efforts to support and maintain a youthful appearance, Stem Cellscan complement these two key elements and contribute to a significant improvement in overall skin tone and texture. Were taking it one step further by introducing you to NASA Stem Cell Technology.This revolutionary technology increases the overall efficacy of stem cells - allowing them to enhance our tried and trusted anti-aging skin care routines in order to seemingly defy gravity.

Stem Cells are naturally produced by our body and have the capacity to split and renew themselves over extended periods of time. This regeneration process is the key to skin rejuvenation as it supports the two key anti-aging elements - cell turnover and collagen production.

Like human stem cells, plant-derived stem cells have antioxidant properties and contain amino acids. Amino acids are the building blocks of proteins which promote cell renewal and maintain our skins overall hydration. However, when stem cells are created for topical application, they tend to flatten and lose efficacy under the influence of gravity.

If youd like to learn more about stem cells in skin care, check out this blog post!

Our Stem Cell Technology is a blend of cultured plant cells created without the influence of gravity, resulting in a powerful technology that is clinically proven to reduce the signs of aging. These cells more closely mimic those that we naturally produce, resulting in an overall increase in benefits.

NASA Stem Cell Technology was designed with a specific focus of targeting the signs of aging on the skin. Its key benefits include reducing the signs of lines and wrinkles, supporting the proliferation of skin cells and preventing/ delaying the visible signs of aging.

What could be more effective than incorporating a powerful technology such as NASAs Stem Cells in skincare? Coupling this key ingredient with clean and effective ingredients that are clinically proven to drive results. As our Director of Brand Development Heather Wilson says, Skin care products should be evaluated as a sum of their parts, not based on a single ingredient. That is why when creating products, we design them to include a combination of powerful actives, alongside a variety of botanicals, to create a formula that offers superior results versus a single ingredient.

Our Anti-Aging Collagen Serumpairs NASA Stem Cell Technology with Hyaluronic Acid, Collagen and a Peptide Complex to firm the appearance of lines and wrinkles to reveal a more vibrant, youthful complexion.

Hyaluronic Acid and Collagen act like a drink of water for the skin, hydrating and plumping the appearance of fine lines and wrinkles while Peptides support a healthy skin barrier and promote collagen production to reduce common signs of aging.

Suitable for all skin types, our Anti-Aging Collagen Serum:

This serum will provide a targeted treatment for deep lines and wrinkles due to its notable concentration of active ingredients in a safe and clean formula. It is lightweight, aroma-free and will appear milky white in color. It can be used both morning and night, after cleansing and before moisturizer.

If youre looking to deeply hydrate your skin and soften the look of fine lines and wrinkles:

Our Hyaluronic Acid Serum 85% pairs NASA Stem Cell Technology with a Multi-Molecular Hyaluronix and Niacinamide to deeply replenish the skin and reveal a more radiant, nourished and youthful complexion.

Multi-Molecular Hyaluronix is a form of Hyaluronic Acid comprised of various molecular weights to hydrate multiple layers of the skin while Niacinamide protects the skins natural barrier. Polyglutamic Acid adds another level of hydration while preventing water loss on the skin.

Suitable for all skin types, our Hyaluronic Acid Serum 85%:

This serum is lightweight, oil-free, aroma-free and will appear pale blue in color. For best results, we recommend shaking this product before use and apply twice a day, both morning and night. Follow up with your favorite moisturizer to seal in the benefits of this targeted treatment.

Our Dark Spot Corrector pairs NASA Stem Cell Technology with Glycolic Acid and Niacinamide to minimize sunspots and hyperpigmentation to reveal a more clear, bright complexion.

Glycolic Acidis an alpha hydroxy acid (AHA) that boosts cell turnover to exfoliate dulling skin cells and smooth the texture of skin. Niacinamide supports a healthy skin barrier while decreasing the appearance of discoloration and redness.

Suitable for all skin types, our Dark Spot Corrector:

This corrector is lightweight, oil-free, aroma-free and vegan. While AHAs provide incredible resurfacing abilities for the skin and are often preferred over physical exfoliants, they can increase our skins sensitivity to the sun. It is recommended that this product is used at night and an appropriate SPF is worn during the day.

For additional tips + tricks on how to fight the first signs of aging check out How to Fight Your First Wrinkles from our Natural Notes.

Stem cells provide the perfect boost to your favorite skin care ingredients to target and treat your anti-aging concerns. So much so that weve launched an entire collection because of it! So, whether youre looking to plump fine lines, reduce hyper pigmentation, or simply prevent future signs of aging - weve got the perfectsolutionfor you!

The rest is here:
The Science in Skin Care Introducing Stem Cell Technology

Fight the signs of premature aging with these stem cell skin care beauty products. A lot of companies claim to incorporate the benefits of plant and human stem cells, as well as components secreted by them, into the best stem cell beauty products on the market. Below, we present what appears (based on company claims) to be ten of the best products available today.

As a publisher of stem cell news, we havent traditionally wandered into the world of claims made by stem cell beauty products suppliers. For obvious reasons, we cannot guarantee the accuracy of the claims made by these companies or the presence of specific active agents within them.

However, we get approached daily with questions about this topic and know that people are seeking information about it from a source that: 1) Doesnt inflate the claims, and 2) Understands the science.

For this reason, we have decided to share with you what appear to be interesting skin care options, coupled with a healthy dose of warnings reminding you that the stated claims may or may not be accurate.

Kimera Labs makes the top of this list for numerous reasons. First, the companys science it is solid. Instead of being a supplier of beauty products, the company is a specialty contract research organization (CRO) focusing on regenerative medicine applications, including exosome purification. Exosomes are small vesicles (~30-100nm) that are secreted by nearly all cell types and act as intracellular mail.

Exosomes transfer DNA, RNA, and proteins to other cells, thereby altering the function of the other cells.

Second, the company has an FDA registered tissue facility in Miami, FL, where it develops pharmaceutical grade, exosome-based regenerative therapies. The company has a 6,000 sq. ft. facility in Miramar, Florida, that includes impressive features such asISO:9001/13485 certification, cleanrooms, and a variety of high-end scientific equipment.

Third, the company is run by Dr. Duncan Ross, a highly regarded scientist with a Ph.D. in Immunology from the University of Miami. Dr. Ross is also a Principal at The Kimera Society, a non-profit organization dedicated to the advancementof stem cells, regenerative medicine,and cancer immunotherapies.

For those seeking stem cell beauty products, the companys core offering is XoGlo, a product which provides growth and healing signals to guide the re-deposition of tissue and avoid the scarring that often accompanies burns or other skin damage. You can see an incredible Case Study from the company in which XoGlo was used to heal second-degree burns in a patient in approximately seven days. The product can also be used for general skin health and enhancement.

More information on the XoGlois available here.

According to the company, this facial cleanser is formulated with stem cytokines that promote the skins ability to heal itself, leaving softer and smoother skin. It also has essential fatty acids, detoxifying actives, antioxidants, and anti-inflammatory botanicals that deeply cleanse your skin of excess oil, impurities, and surface debris. This makes the skin smoother, more balanced, and hydrated.

Lifeline says that it offers a moisture serum with a formula consisting of proteins and peptides from pluripotent stem cells. It works by reversing skin aging signs and actively moisturizing the skin with its cucumber melon extracts. The serum primarily targets the reduction of wrinkles and fine lines.

At $105 for a 1 oz bottle, it is notable that the company does not mention how it sources pluripotent stem cells, leaving key questions about its active ingredients unanswered.

Heres another skin care serum on this list of stem cellbeauty products. This serum is enriched with a tissue nutrient solution (TNS) technology that reduces wrinkles and fine lines and improves skin texture and tone. TNS is formulated with matrix proteins, cytokines, soluble collagen, antioxidants, and growth factors that are essential to keeping skin healthy.

This regenerative eye creamcontains autokine-CM obtained from adult stem cells through mini-liposuction. This unique ingredient is composed of extracted cytokines, matrix proteins, and growth factors from adult stem cells that help improve the skins ability to heal. It also aids in synthesizing elastin and collagen production, thus reducing fine lines and wrinkles, improving skin tone and texture, and increasing epidermal thickness in the eye area.

Venus Skin introduced a stem cell therapy serum packed with bio-signals from bone marrow mesenchymal stem cells for stimulation of skin tissue repair and healing. This reverses aging signs and rejuvenates the feel and look of the skin. It also contains essential vitamins A, C, and E to normalize skin functions, promote collagen synthesis in the skin, and reduce the appearance of scars, respectively.

This hydrating mask possesses a stem cell culture technology that penetrates deep into the skin for intense and long-lasting hydration. This leaves the skin well-moisturized and supple. It also fills fine lines and wrinkles and restores parched skin, bringing skin moisture and smoothness back.

This intensive facial mist restores the skins elasticity and moisture with its fine liquid particles that immediately penetrate the skin. It contains APL stem cell-conditioned medium extracts that help regenerate, whiten, and hydrate the skin and minimize pores and wrinkles. The facial mist also has chamomile extracts that bring a soothing effect to the skin.

Skin Drink Phytoceuticals highlights three potent anti-aging skin care ingredients in this serum.PhytoCellTec is an ingredient that safeguards the skin stem cells longevity, fights off skin aging, and delays biological aging of cells. Derm SRC works on reducing wrinkles and fine lines, while Ellagi-C promotes skin elasticity and suppleness.

This snail serum boasts an epidermal growth factor ingredient that stimulates the skins stem cell growth and cell survival. It also has a snail mucus extract that refreshes and brightens the skin. Aside from that, the serum contains other natural ingredients, such as macadamia seed oil and hydrolyzed placenta extract, for skin hydration and nourishment.

Which of these components actually enhance skin health and complexion? Hard to say, but the ingredient list certainly is exotic.

With this list of the best beauty products, it can be tricky to know which ones will enhance skin health. Stem cells are becoming a common ingredient in skin products, but regulation of this area is sparse, making it important to be vigilant in your selection.

A steep price tag doesnt guarantee results. Claims of active ingredients do not guarantee they are present. Even the confirmed presence of an ingredient by third-party testing does not substantiate its claimed effect.

However, there are hundreds of user reviews for some of these products, so the possibility for these skin care products to improve the appearance of your skin does exist. Importantly, many of these stem cell beauty products contain an impressive range of other ingredients, so you could benefit from them due to effects unrelated to the claimed stem cell components.

When judging the efficacy of these products, the only clear answer is that you need to be your own study of one.

Let this infographic be your guide. Download it now and use it as a reference later.

If you found this article valuable, subscribe to BioInformantsstem cell industry updates.We are the industry leaders in stem cell research, with research cited byThe Wall Street Journal, Xconomy, AABB, andVogue Magazine.Bringing you breaking news on an ongoing basis, join nearly aa million loyal readers, including physicians, scientists, executives, investors, and philanthropists.

Do you have questions about whether a stem cell treatment could address your medical condition?

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10 Best Stem Cell Beauty Products On The Market Today

She just wanted to be somewhere safe, somewhere familiar, where people looked and spoke like her and she could stand to eat the food. Midnight Robber by Nalo Hopkinson

Midnight Robber (2000) is about a woman, divided. Raised on the high-tech utopian planet of Touissant, Tan-Tan grows up on a planet populated by the descendants of a Caribbean diaspora, where all labor is performed by an all-seeing AI. But when she is exiled to Touissants parallel universe twin planet, the no-tech New Half-Way Tree, with her sexually abusive father, she becomes divided between good and evil Tan-Tans. To make herself and New Half-Way Tree whole, she adopts the persona of the legendary Robber Queen and becomes a legend herself. It is a wondrous blend of science fictional tropes and Caribbean mythology written in a Caribbean vernacular which vividly recalls the history of slavery and imperialism that shaped Touissant and its people, published at a time when diverse voices and perspectives within science fiction were blossoming.

Science fiction has long been dominated by white, Western perspectives. Vernes tech-forward adventures and Wells sociological allegories established two distinctive styles, but still centered on white imperialism and class struggle. Subsequent futures depicted in Verne-like pulp and Golden Age stories, where lone white heroes conquered evil powers or alien planets, mirrored colonialist history and the subjugation of non-white races. The civil rights era saw the incorporation of more Wellsian sociological concerns, and an increase in the number of non-white faces in the future, but they were often tokensparts of a dominant white monoculture. Important figures that presaged modern diversity included Star Treks Lieutenant Uhura, played by Nichelle Nichols. Nichols was the first black woman to play a non-servant character on TV; though her glorified secretary role frustrated Nichols, her presence was a political act, showing there was space for black people in the future.

Another key figure was the musician and poet Sun Ra, who laid the aesthetic foundation for what would become known as the Afrofuturist movement (the term coined by Mark Dery in a 1994 essay), which showed pride in black history and imagined the future through a black cultural lens. Within science fiction, the foundational work of Samuel Delany and Octavia Butler painted realistic futures in which the histories and cultural differences of people of color had a place. Finally, an important modern figure in the decentralization of the dominant Western perspective is Nalo Hopkinson.

A similarly long-standing paradigm lies at the heart of biology, extending back to Darwins theoretical and Mendels practical frameworks for the evolution of genetic traits via natural selection. Our natures werent determined by experience, as Lamarck posited, but by genes. Therefore, genes determine our reproductive fitness, and if we can understand genes, we might take our futures into our own hands to better treat disease and ease human suffering. This theory was tragically over-applied, even by Darwin, who in Descent of Man (1871) conflated culture with biology, assuming the Wests conquest of indigenous cultures meant white people were genetically superior. After the Nazis committed genocide in the name of an all-white future, ideas and practices based in eugenics declined, as biological understanding of genes matured. The Central Dogma of the 60s maintained the idea of a mechanistic meaning of life, as advances in genetic engineering and the age of genomics enabled our greatest understanding yet of how genes and disease work. The last major barrier between us and our transhumanist future therefore involved understanding how genes determine cellular identity, and as well see, key figures in answering that question are stem cells.

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Hopkinson was born December 20, 1960 in Kingston, Jamaica. Her mother was a library technician and her father wrote, taught, and acted. Growing up, Hopkinson was immersed in the Caribbean literary scene, fed on a steady diet of theater, dance, readings, and visual arts exhibitions. She loved to readfrom folklore, to classical literature, to Kurt Vonnegutand loved science fiction, from Spock and Uhura on Star Trek, to Le Guin, James Tiptree Jr., and Delany. Despite being surrounded by a vibrant writing community, it didnt occur to her to become a writer herself. What they were writing was poetry and mimetic fiction, Hopkinson said, whereas I was reading science fiction and fantasy. It wasnt until I was 16 and stumbled upon an anthology of stories written at the Clarion Science Fiction Workshop that I realized there were places where you could be taught how to write fiction. Growing up, her family moved often, from Jamaica to Guyana to Trinidad and back, but in 1977, they moved to Toronto to get treatment for her fathers chronic kidney disease, and Hopkinson suddenly became a minority, thousands of miles from home.

Development can be described as an orderly alienation. In mammals, zygotes divide and subsets of cells become functionally specialized into, say, neurons or liver cells. Following the discovery of DNA as the genetic material in the 1950s, a question arose: did dividing cells retain all genes from the zygote, or were genes lost as it specialized? British embryologist John Gurdon addressed this question in a series of experiments in the 60s using frogs. Gurdon transplanted nuclei from varyingly differentiated cells into oocytes stripped of their genetic material to see if a new frog was made. He found the more differentiated a cell was, the lower the chance of success, but the successes confirmed that no genetic material was lost. Meanwhile, Canadian biologists Ernest McCulloch and James Till were transplanting bone marrow to treat irradiated mice when they noticed it caused lumps in the mices spleens, and the number of lumps correlated with the cellular dosage. Their lab subsequently demonstrated that each lump was a clonal colony from a single donor cell, and a subset of those cells was self-renewing and could form further colonies of any blood cell type. They had discovered hematopoietic stem cells. In 1981 the first embryonic stem cells (ESCs) from mice were successfully propagated in culture by British biologist Martin Evans, winning him the Nobel Prize in 2007. This breakthrough allowed biologists to alter genes in ESCs, then use Gurdons technique to create transgenic mice with that alteration in every cellcreating the first animal models of disease.

In 1982, one year after Evans discovery, Hopkinson graduated with honors from York University. She worked in the arts, as a library clerk, government culture research officer, and grants officer for the Toronto Arts Council, but wouldnt begin publishing her own fiction until she was 34. [I had been] politicized by feminist and Caribbean literature into valuing writing that spoke of particular cultural experiences of living under colonialism/patriarchy, and also of writing in ones own vernacular speech, Hopkinson said. In other words, I had models for strong fiction, and I knew intimately the body of work to which I would be responding. Then I discovered that Delany was a black man, which opened up a space for me in SF/F that I hadnt known I needed. She sought out more science fiction by black authors and found Butler, Charles Saunders, and Steven Barnes. Then the famous feminist science fiction author and editor Judy Merril offered an evening course in writing science fiction through a Toronto college, Hopkinson said. The course never ran, but it prompted me to write my first adult attempt at a science fiction story. Judy met once with the handful of us she would have accepted into the course and showed us how to run our own writing workshop without her. Hopkinsons dream of attending Clarion came true in 1995, with Delany as an instructor. Her early short stories channeled her love of myth and folklore, and her first book, written in Caribbean dialect, married Caribbean myth to the science fictional trappings of black market organ harvesting. Brown Girl in the Ring (1998) follows a young single mother as shes torn between her ancestral culture and modern life in a post-economic collapse Toronto. It won the Aspect and Locus Awards for Best First Novel, and Hopkinson was awarded the John W. Campbell Award for Best New Writer.

In 1996, Dolly the Sheep was created using Gurdons technique to determine if mammalian cells also could revert to more a more primitive, pluripotent state. Widespread animal cloning attempts soon followed, (something Hopkinson used as a science fictional element in Brown Girl) but it was inefficient, and often produced abnormal animals. Ideas of human cloning captured the public imagination as stem cell research exploded onto the scene. One ready source for human ESC (hESC) materials was from embryos which would otherwise be destroyed following in vitro fertilization (IVF) but the U.S. passed the Dickey-Wicker Amendment prohibited federal funding of research that destroyed such embryos. Nevertheless, in 1998 Wisconsin researcher James Thomson, using private funding, successfully isolated and cultured hESCs. Soon after, researchers around the world figured out how to nudge cells down different lineages, with ideas that transplant rejection and genetic disease would soon become things of the past, sliding neatly into the hole that the failure of genetic engineering techniques had left behind. But another blow to the stem cell research community came in 2001, when President Bushs stem cell ban limited research in the U.S. to nineteen existing cell lines.

In the late 1990s, another piece of technology capturing the public imagination was the internet, which promised to bring the world together in unprecedented ways. One such way was through private listservs, the kind used by writer and academic Alondra Nelson to create a space for students and artists to explore Afrofuturist ideas about technology, space, freedom, culture and art with science fiction at the center. It was wonderful, Hopkinson said. It gave me a place to talk and debate with like-minded people about the conjunction of blackness and science fiction without being shouted down by white men or having to teach Racism 101. Connections create communities, which in turn create movements, and in 1999, Delanys essay, Racism and Science Fiction, prompted a call for more meaningful discussions around race in the SF community. In response, Hopkinson became a co-founder of the Carl Brandon society, which works to increase awareness and representation of people of color in the community.

Hopkinsons second novel, Midnight Robber, was a breakthrough success and was nominated for Hugo, Nebula, and Tiptree Awards. She would also release Skin Folk (2001), a collection of stories in which mythical figures of West African and Afro-Caribbean culture walk among us, which would win the World Fantasy Award and was selected as one ofThe New York Times Best Books of the Year. Hopkinson also obtained masters degree in fiction writing (which helped alleviate U.S. border hassles when traveling for speaking engagements) during which she wrote The Salt Roads (2003). I knew it would take a level of research, focus and concentration I was struggling to maintain, Hopkinson said. I figured it would help to have a mentor to coach me through it. That turned out to be James Morrow, and he did so admirably. Roads is a masterful work of slipstream literary fantasy that follows the lives of women scattered through time, bound together by the salt uniting all black life. It was nominated for a Nebula and won the Gaylactic Spectrum Award. Hopkinson also edited anthologies centering around different cultures and perspectives, including Whispers from the Cotton Tree Root: Caribbean Fabulist Fiction (2000), Mojo: Conjure Stories (2003), and So Long, Been Dreaming: Postcolonial Science Fiction & Fantasy (2004). She also came out with the award-winning novelThe New Moons Arms in 2007, in which a peri-menopausal woman in a fictional Caribbean town is confronted by her past and the changes she must make to keep her family in her life.

While the stem cell ban hamstrung hESC work, Gurdons research facilitated yet another scientific breakthrough. Researchers began untangling how gene expression changed as stem cells differentiated, and in 2006, Shinya Yamanaka of Kyoto University reported the successful creation of mouse stem cells from differentiated cells. Using a list of 24 pluripotency-associated genes, Yamanaka systematically tested different gene combinations on terminally differentiated cells. He found four genesthereafter known as Yamanaka factorsthat could turn them into induced-pluripotent stem cells (iPSCs), and he and Gurdon would share a 2012 Nobel prize. In 2009, President Obama lifted restrictions on hESC research, and the first clinical trial involving products made using stem cells happened that year. The first human trials using hESCs to treat spinal injuries happened in 2014, and the first iPSC clinical trials for blindness began this past December.

Hopkinson, too, encountered complications and delays at points in her career. For years, Hopkinson suffered escalating symptoms from fibromyalgia, a chronic disease that runs in her family, which interfered with her writing, causing Hopkinson and her partner to struggle with poverty and homelessness. But in 2011, Hopkinson applied to become a professor of Creative Writing at the University of California, Riverside. It seemed in many ways tailor-made for me, Hopkinson said. They specifically wanted a science fiction writer (unheard of in North American Creative Writing departments); they wanted someone with expertise working with a diverse range of people; they were willing to hire someone without a PhD, if their publications were sufficient; they were offering the security of tenure. She got the job, and thanks to a steady paycheck and the benefits of the mild California climate, she got back to writing. Her YA novel, The Chaos (2012), coming-of-age novelSister Mine (2013), and another short story collection, Falling in Love with Hominids (2015) soon followed. Her recent work includes House of Whispers (2018-present), a series in DC Comics Sandman Universe, the final collected volume of which is due out this June. Hopkinson also received an honorary doctorate in 2016 from Anglia Ruskin University in the U.K., and was Guest of Honor at 2017 Worldcon, a year in which women and people of color dominated the historically white, male ballot.

While the Yamanaka factors meant that iPSCs became a standard lab technique, iPSCs are not identical to hESCs. Fascinatingly, two of these factors act together to maintain the silencing of large swaths of DNA. Back in the 1980s, researchers discovered that some regions of DNA are modified by small methyl groups, which can be passed down through cell division. Different cell types have different DNA methylation patterns, and their distribution is far from random; they accumulate in the promoter regions just upstream of genes where their on/off switches are, and the greater the number of methyl groups, the lesser the genes expression. Furthermore, epigenetic modifications, like methylation, can be laid down by our environments (via diet, or stress) which can also be passed down through generations. Even some diseases, like fibromyalgia, have recently been implicated as such an epigenetic disease. Turns out that the long-standing biological paradigm that rejected Lamarck also missed the bigger picture: Nature is, in fact, intimately informed by nurture and environment.

In the past 150 years, we have seen ideas of community grow and expand as the world became more connected, so that they now encompass the globe. The histories of science fiction and biology are full of stories of pioneers opening new doorsbe they doors of greater representation or greater understanding, or bothand others following. If evolution has taught us anything, its that nature abhors a monoculture, and the universe tends towards diversification; healthy communities are ones which understand that we are not apart from the world, but of it, and that diversity of types, be they cells or perspectives, is a strength.

Kelly Lagor is a scientist by day and a science fiction writer by night. Her work has appeared at Tor.com and other places, and you can find her tweeting about all kinds of nonsense @klagor

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On the Origins of Modern Biology and the Fantastic: Part 19 Nalo Hopkinson and Stem Cell Research - tor.com

INTRODUCTION

A ganglion is a cluster or group of nerve cells found in the peripheral nervous system (PNS) or central nervous system (CNS). They often interconnect with each other and with other structures in the PNS and CNS to form a complex nervous network. There are three groups of ganglia in the PNS, which are the dorsal root ganglia (DRG), cranial nerve ganglia, and autonomic ganglia, and two types of ganglia in the CNS, which are the basal ganglia in the brain and retinal ganglion in the retina. Unlike other ganglia, which are essentially cell clusters, retinal ganglia consist of a layer/sheet of dispersive retinal ganglion cells (RGCs). Diverse types of neurons in the somatosensory ganglia such as DRG are specialized for different sensory modalities such as proprioception, mechanoreception, nociception (i.e., pain perception), thermoception, and pruriception (i.e., itch perception) (1, 2). Similarly, there are numerous subtypes of RGCs that are specialized for transmitting from the retina different visual information (e.g., color, contrast, and motion direction) to the central visual system in the brain (3). In the human, a variety of pain, itch, neurological, and degenerative disorders affect sensory ganglia (SGs) and RGCs. Mutations in the FXN (frataxin) and IKBKAP genes, for example, result in debilitating Friedreichs ataxia and familial dysautonomia, respectively (4, 5). Dominant gain-of-function mutations in the sodium channel Nav1.7 gene SCN9A, which is expressed in sensory neurons, are linked to two severe pain syndromesinherited erythromelalgia and paroxysmal extreme pain disorder, while its recessive loss-of-function mutations cause dangerous congenital insensitivity to pain (6). Recently, peripheral SG dysfunction has also been linked to tactile sensitivity and other behavioral deficits associated with the autism spectrum disorders (7). Both genetic and environmental risk factors contribute to glaucoma, which is a leading cause of blindness worldwide and characterized by progressive degeneration of RGCs and the optic nerve (8).

Despite the difference in morphology and embryonic origin, somatosensory and retinal ganglia share extensive overlap of gene expression and we proposed more than two decades back that both might also share genetic regulatory hierarchies (9, 10). This assumption has largely turned out to be the case. During embryogenesis, somatosensory ganglion neurons arise from the multipotent neural crest (NC) cells through a process of cell migration and coalescence (1). RGCs are also derived from multipotent retinal progenitor cells and destined to the ganglion cell layer by migration. It has been shown that the neurogenic bHLH transcription factors (TFs) Ngn1 and/or Ngn2 are involved in the determination of peripheral sensory neurons (11), and that the homeodomain TFs Isl1 and Brn3a or Brn3b are required for the specification and differentiation of different subtypes of neurons in the somatosensory and retinal ganglia (1217). Moreover, there is substantial functional redundancy between Ngn1 and Ngn2 as well as between Brn3a and Brn3b in the development of sensory neurons and RGCs (11, 18, 19).

Somatic cell reprogramming by defined TFs into sensory neurons provides a powerful strategy for studying mechanisms of SG development and sensory disease pathogenesis and for generating cells for patient-specific cell replacement therapy, drug screening, and in vitro disease modeling. It has been shown recently that nociceptor and other subtypes of sensory neurons can be directly induced from murine and human fibroblasts by Brn3a and Ngn1 or Ngn2 or by a combination of five TFs including Ascl1, Ngn1, Isl2, Myt1l, and Klf7 (20, 21). The induced sensory neurons express characteristic marker proteins and are electrically active and selectively responsive to various agonists known to activate pain- and itch-sensing neurons (20, 21). However, networked SG did not appear to be consistently generated in these cases, and it is unclear whether RGCs were induced by these combinations of TFs.

Given the advantages of organoids in studying developmental mechanisms and modeling and treating relevant diseases, we sought to generate ganglion organoids and RGCs from mouse and human fibroblasts using TFs controlling in vivo development of sensory and retinal ganglia. The extensive molecular homology between SG neurons and RGCs creates a dilemma as to how to distinguish these two types of neurons. In the past, several RGC markers including Brn3a, Brn3b, Isl1, Thy1.2, Sncg, Math5, Rbpms, and RPF-1 were used to identify RGCs induced from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and somatic cells (2225). However, this is a questionable practice because although these markers are sufficient to identify RGCs within the retina, they are inadequate as specific markers for identifying induced RGCs (iRGCs), given their expression in SG and other CNS regions as well (10, 15). We thus carefully screened for RGC-specific markers by comparing expression patterns of numerous known markers in the retina and DRG. This analysis revealed Pax6 expression in RGCs but not in DRG and that RGCs can be identified as Pax6+Brn3a+ or Pax6+Brn3b+ double-positive cells. Equipped with this knowledge, we set to generate induced SG (iSG) organoids and iRGCs from fibroblasts by testing the combination of Ascl1, the pioneer neurogenic TF for somatic cell reprogramming of neurons (26), with a variety of SG and retinal TFs. This screen identified a triple-factor combination ABI (Ascl1-Brn3a/3b-Isl1) as the most efficient way to induce self-organized and networked iSG and iRGCs from fibroblasts.

Previous studies by our group and others have demonstrated that SGs and RGCs share similar transcriptional regulatory mechanism for their development, for instance, both Brn3 TFs (Brn3a and Brn3b) and Isl1 are involved in the specification and differentiation of DRG neurons and RGCs (1214, 16). More recently, Ascl1 has been shown to play a pioneering role in induced neuron (iN) reprogramming from somatic cells (26). As a first step to generate iSG and iRGCs directly from somatic cells, we sought to induce SG neurons and RGCs from mouse embryonic fibroblasts (MEFs) by testing the combination of Ascl1 with each of 22 SGs and retinal TFs (Brn3b, Isl1, Math5, Ebf1, Pax6, Tfap2a, Nr4a2, Nrl, Crx, Ptf1a, Neurod1, Lhx2, Ngn1, Ngn2, Chx10, Sox2, Rx, Meis1, Foxn4, Otx2, Sox9, and Six3). When MEFs were infected with doxycycline (Dox)inducible Ascl1 and Brn3b (AB) or Isl1 (AI) lentiviruses and cultured in the neural differentiation medium containing Dox, they started to change morphology by day 7 and form visible neuronal clusters by day 14 (Fig. 1, C and D). This phenomenon did not occur when Ascl1 acted alone or was combined with each of the rest of 20 TFs (Fig. 1B). Neither did this happen when MEFs were infected with both Brn3b and Isl1 viruses or with only control green fluorescent protein (GFP) viruses (Fig. 1, A and E). When we combined Ascl1 with both Brn3b and Isl1 (ABI), they again induced morphological changes of MEFs but more importantly induced conspicuously more neuronal clusters than either the AB or AI double-factor combinations (Fig. 1, C, D, F, and N, and fig. S1, A and B), suggesting a synergistic effect between Brn3b and Isl1 in reprogramming MEFs into neuronal clusters.

(A to I) Morphological changes of MEFs infected with the indicated lentiviruses (A, Ascl1; B, Brn3b; I, Isl1) and cultured for 14 days. Networked iSGs were induced by combinations of Ascl1 with Brn3b (AB), Isl1 (AI), or both Brn3b and Isl1 (ABI), with the ABI triple-factor combination as the most efficient. Arrows point to the thick fasciculated nerve fibers interconnecting iSG. Scale bars, 160 m (A to F) and 80 m (G to I). (J to M) Scattered iNs and clustered iSG induced by AI, ABI, A, or BAM (Brn2 + Ascl1 + Myt1l) were immunolabeled for Tuj1 and counterstained with nuclear 4,6-diamidino-2-phenylindole (DAPI). Note the morphological differences of Tuj1-immunoreactive neurons between conditions. Scale bars, 40 m. (N) Quantification of iSG induced by single and combinations of TFs. MEFs (6 104) were seeded into each well of 12-well plates and infected with lentiviruses expressing the indicated TFs or GFP, and iSGs in each well were then counted at day 14 following virus infection. Data are means SD (n = 3). Asterisks indicate significance in one-way analysis of variance test: *P < 0.0001. (O) Snapshots of a time-lapse video showing how individual neurons induced by ABI self-organized into an iSG. The arrow, arrowhead, and asterisk indicate the positions of three individual iNs at different time points. Scale bar, 62.5 m. (P) Schematic indicating the outcome (iNs or iSG) of MEFs induced by BAM, AI, AB, or ABI.

The neuronal clusters induced by either double- or triple-factor combinations (AB, AI, and ABI) appeared to be interconnected by thick fasciculated nerve fibers and resemble SG plexus in morphology (Fig. 1, G to I) and thus were designated as iSG organoids. The iSG neurons and associated nerve fibers were highly immunoreactive for the neuronal marker Tuj1 (Fig. 1, J and K, and fig. S2, D to I). Tuj1 immunolabeling also showed that AI- and ABI-induced neurons mostly formed iSG, and only a small number of them were scattered outside the iSG (Fig. 1, J, K, and P). By contrast, Tuj1 immunoreactivity showed that Ascl1 alone induced neurons mostly with an immature morphology and that the BAM (Brn2, Ascl1, and Mytl1) combination induced mature neurons that were scattered instead of clustered (Fig. 1, L, M, and P, and fig. S2, A to C), consistent with previous reports (27). Therefore, we identified the AB, AI, and ABI combinations of TFs capable of inducing MEFs into iSG, with the ABI triple-factor combination as the most efficient.

To investigate how ABI-reprogrammed neurons are organized into iSG, we used long-term time-lapse microscopy to track them over time in culture. For this purpose, MEFs were prepared from the CAG-GFP transgenic mouse embryos (28) and induced by ABI for 10 days before time-lapse recording. Compared to MEFs, reprogrammed individual neurons appeared to be rounder and neurite-bearing and displayed much higher contrast and brighter GFP fluorescence (Fig. 1O and movies S1 and S2). Over a period of tens of hours, they first formed smaller cellular clusters via migration, which then coalesced into bigger and bigger clusters that resembled SG. We did not observe this self-organization phenomenon for neurons induced by Ascl1 (movies S3 and S4).

The induction of iSG by TFs from MEFs could be through direct cell conversion or might be mediated through an intermediate proliferative progenitor. To distinguish these possibilities, we pulse-labeled cells with 5-ethynyl-2-deoxyuridine (EdU) for 24 hours at day 14 of reprogramming with AI or ABI and found that almost no Tuj1-positive cells were labeled by EdU, whereas approximately 15% of Tuj1-negative cells (e.g., MEFs) were labeled (fig. S2, G to J and N to P). We then reprogrammed MEFs with ABI in the presence of EdU for 13 days starting from day 1 of reprogramming. In this case, only 6.1% of Tuj1-positive cells were labeled by EdU, whereas 73.1% of Tuj1-negative cells were labeled (fig. S2, J to M), suggesting that iSGs are most likely induced by direct cell transdifferentiation without undergoing a proliferative intermediate state. In agreement with these results, as determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays, we detected no increase of expression levels of the neural progenitor marker genes Nestin and Olig2 over the entire time course (from day 1 to day 12) of ABI reprogramming (fig. S2Q). Similarly, the expression of pluripotent factor genes Oct4, Klf4, and Nanog was not induced during the time course of ABI reprogramming (fig. S2R). Furthermore, immunostaining showed that from day 1 to day 12 of ABI reprogramming, no protein expression was seen for the neural progenitor marker Nestin, pluripotent progenitor markers Nanog and Oct4, or Sox2, a marker for both neural and pluripotent progenitor cells (fig. S2, S and T). Thus, iSGs are most likely induced by direct cell transdifferentiation without undergoing an intermediate state of neural or pluripotent progenitors.

Given the demonstrated functional redundancy and similar DNA binding and transcriptional properties between Brn3a and Brn3b (10, 18, 19), we investigated whether these two factors are interchangeable in somatic cell reprogramming. We tested whether Brn3a was able to replace Brn3b in reprogramming MEFs into iSG and found that this indeed was the case (Fig. 1N and fig. S3, A to I).

By immunofluorescent staining and qRT-PCR assays, we examined a variety of molecular neuronal markers, both general and cell type specific, to characterize the iSG reprogrammed from MEFs by ABI (Ascl1 + Brn3b + Isl1 or Ascl1 + Brn3a + Isl1). We found that they were highly immunoreactive for Tuj1 and Map2 (Fig. 2, A and O), two general neuronal hallmarks. They also expressed synapsin and Vamp (synaptobrevin) (Fig. 2, B and C), suggesting that the networked iSG neurons were capable of forming synapses and releasing synaptic vesicles. In the normal SG, the heavy neurofilament NF200 and intermediate neurofilament peripherin are expressed in the A-fiber and C-fiber neurons, respectively, and both were seen to be expressed in the iSG (Fig. 2, D, E, and P). Many neurons in the iSG were also immunoreactive for the vesicular glutamate transporters 1 and 2 (vGLUT1 and vGLUT2) (Fig. 2, F and G), consistent with the fact that peripheral sensory neurons are mostly excitatory glutamatergic neurons. As determined by qRT-PCR, these immunolabeling results were confirmed by the marked up-regulation of expression of Tuj1, Map2, NF200, vGlut1, vGlut2, and vGlut3 genes in the ABI-induced iSG compared to MEFs infected by GFP lentiviruses (Fig. 2W).

(A to P) iSGs induced by Ascl1, Brn3b, and Isl1 (A to N) or Ascl1, Brn3a, and Isl1 (O and P) were double-immunostained with the indicated antibodies and counterstained with nuclear DAPI. They were immunoreactive for Tuj1, Map2, synapsin, Vamp, NF200, peripherin, vGLUT1, vGLUT2, TrkA, TrkB, TrkC, c-Ret, TH, p75NTR, and Brn3a. Scale bars, 80 m (A) and 40 m (B to P). (Q to V) Sections from iSG induced by Ascl1, Brn3b, and Isl1 were immunostained with the indicated antibodies and counterstained with nuclear DAPI. Scale bars, 12.7 m. (W) qRT-PCR analysis showing that in MEFs infected with ABI (Ascl1 + Brn3b + Isl1) viruses, compared to those infected with GFP viruses, there was a significant increase in expression of the indicated genes, which represent general and subtype-specific sensory neuron markers. Data are means SD (n = 3 or 4). Asterisks indicate significance in unpaired two-tailed Students t test: *P < 0.05, **P < 0.001, ***P < 0.0001. (X) qRT-PCR analysis showing that in MEFs infected with ABI viruses, compared to those infected with GFP viruses, there was a significant increase in expression of the indicated genes, which represent nociception pathway genes of sensory neurons. Data are means SD (n = 3 or 4). Asterisks indicate significance in unpaired two-tailed Students t test: *P < 0.05, **P < 0.005, ***P < 0.0005. (Y) Quantification of Tuj1-positive neurons that express each of the three Trk receptors (TrkA, TrkB, or TrkC) individually or combined (TrkABC) in MEFs infected with the ABI viruses. Data are means SD (n = 3).

In the DRG, neurotrophin receptor expression marks subtypes of sensory neurons. For instance, TrkA is expressed by cutaneous nociceptive and thermoceptive neurons, TrkB by a subset of cutaneous mechanoreceptive neurons, and TrkC by proprioceptive neurons (1). In the iSG reprogrammed by ABI, qRT-PCR assays revealed that there was a significant up-regulation of TrkA, TrkB, and TrkC gene expression (Fig. 2W). Moreover, immunolabeling confirmed the presence of TrkA, TrkB, and TrkC proteins in both somas and nerve fibers of the induced ganglion neurons (Fig. 2, H to J). Each of the Trk receptors was found in approximately 30% of the iNs, and 87% of the iNs were labeled by costaining for all three Trk receptors (Fig. 2Y), suggesting that each Trk receptor was expressed in a distinct subpopulation of induced ganglion neurons. c-Ret and TH are expressed in subpopulations of nonpeptidergic nociceptors and C-low threshold mechanoreceptors, respectively (1, 2). Correspondingly, we observed expression of both proteins in the iSG and associated nerve fibers (Fig. 2, K and L). In addition, pan-sensory neuron markers Brn3a (for iSG induced by Ascl1 + Brn3b + Isl1) and the nerve growth factor (NGF) receptor p75NTR were also found in iSG neurons (Fig. 2, M and N). qRT-PCR validated the up-regulation of Brn3a and p75NTR expression in the iSG and additionally revealed up-regulation of CGRP, a marker for a subpopulation of peptidergic nociceptive neurons (Fig. 2W).

The TrkA-positive nociceptive neurons in the iSG were further characterized by qRT-PCR analysis. In the iSG, we found significantly up-regulated expression of receptor ion channel genes Trpv1/2/3 and Trpa1, which detect heat and cold, respectively (Fig. 2X) (29). There was also expression of P2X3, Bdkrb1, and Accn1/2, which are receptor genes responsible for damage sensing (Fig. 2X) (29). In addition, induced expression was observed for other pain perception pathway genes including sodium channel gene Scn11a, potassium channel gene Kcnq2, calcium channel genes Cacna1a and Cacna2d1, and neurotransmitter receptor genes Gria1 and Nk1r (Fig. 2X) (29). To further investigate whether distinct types of sensory neurons were aggregated together within the same iSG, we carried out immunostaining analyses of cryosections of ABI-induced iSG. Besides colabeling between Tuj1 and Brn3a in the same iSG, we found that peripherin+ and HuC/D+ neurons, P2X3+ and vGLUT2+ neurons, and TrkA+ and TrkB+ neurons coexisted in the same iSG (Fig. 2, Q to T). Moreover, we detected coexpression of three markers, such as TrkA, P2X3 and NF200, and TrkA, peripherin, and HuC/D, in the same iSG (Fig. 2, U and V), suggesting that individual iSGs are likely aggregated from distinct sensory neuron types.

Over the time course of ABI reprogramming, qRT-PCR assays showed that the expression of general neuronal marker genes Tuj1 and Map2 was progressively induced starting from day 3, whereas other sensory neuronal marker genes including Trpv2, TrkC, and Brn3a were not induced until day 6 or 9 (fig. S1, C to E). Consistent with this, Brn3a-immunoreactive cells did not emerge until day 6 with a mostly scattered pattern, but by day 9 or 12, they mostly coalesced into iSG (fig. S1G). Therefore, as expected, sensory neuronal markers were induced slightly later than general neuronal markers during ABI reprogramming. Concomitant with neuronal induction, the fibroblast marker genes Col1a1 and Twist2 were gradually down-regulated starting from day 3 (fig. S1F).

Immunostaining of iSG induced by AI or AB suggested that they also contained neurons that expressed typical sensory neuronal markers Tuj1, Map2, Dcx (doublecortin), synapsin, NF200, peripherin, vGLUT1, TrkA, TH, HuC/D, and Brn3a (fig. S3, J to S). Together, these data indicate that certain combinations of TFs (ABI, AI, and AB) are capable of reprogramming MEFs into iSG that contain proprioceptive, mechanoreceptive, nociceptive, and thermoceptive sensory neurons.

To assess the electrophysiological properties of neurons within and outside the iSG reprogrammed from MEFs by ABI or AI, we performed whole-cell patch-clamp recordings of cells with neuronal morphology (Fig. 3A). Following 9 days of induction, the recorded neurons (two of two) generated potassium currents and small sodium currents but no action potentials, suggesting that they were functionally immature. At 2 weeks, the great majority of neurons (34 of 37) had typical sodium and potassium currents and exhibited action potential responses (Fig. 3, B to F). Among them, most (70.3%) are multispiking neurons, and the rest (21.6%) are single-spiking (Fig. 3, B, C, E, and K), similar to those reprogrammed from human fibroblasts by Brn3a and Ngn1 or Ngn2 (21). The inward sodium current could be specifically blocked by tetrodotoxin (TTX) and recovered by its removal (Fig. 3, H to J). Moreover, consistent with the synapsin immunoreactivity (Fig. 2B and fig. S3L), some neurons (2 of 37) exhibited spontaneous postsynaptic currents (Fig. 3G), suggesting the formation of functional synapses between iNs. Therefore, the iSG neurons induced by ABI or AI display membrane and physiological properties of mature neurons.

(A) Micrograph showing a typical iSG neuron chosen for patch-clamp recording. (B to D) Current-clamp recordings revealed multiple action potential responses (multiple-spiking) of a differentiated iSG neuron under current injection (B and C). Voltage-clamp recordings of the same neuron indicated fast activated and inactivated inward sodium currents as well as outward potassium currents (D). (E and F) Current injection revealed a single action potential response (single-spiking) of an iSG neuron (E). Voltage-clamp recordings of the same neuron indicated fast activated and inactivated inward sodium currents as well as outward potassium currents (F). (G) Spontaneous postsynaptic currents recorded from a differentiated iSG neuron. (H to J) The sodium currents of an iSG neuron were completely blocked by TTX and were partially restored by its washout. (K) Observed ratios of iSG neurons that are multiple-spiking and single-spiking, or display no action potential (AP). (L to N) iSG induced by ABI and corresponding fluorescent signals after incubation with Fluo-8 AM. Scale bars, 20 m. (O to Q) Calcium changes indicated by fluorescent intensity in normal Ringers solution (O), 10 M capsaicin (P), and 100 mM KCl (Q). Scale bars, 20 m. (R) Representative calcium responses to 100 M menthol and 100 mM KCl. Calcium responses were calculated as the change in fluorescence (F) over the initial baseline fluorescence (F0). (S) Representative calcium responses to 10 M capsaicin and 100 mM KCl. (T and U) Scatter dot plots showing the positive responses of individual cells to menthol, capsaicin, or KCl. Data are means SEM (n = 19 to 44).

The nociceptive sensory neurons express ion channels Trpv1, Trpm8, and Trpa1, which respond to heat, cold, and noxious chemicals, respectively (29). By calcium imaging, we used specific agonists capsaicin (10 M) and menthol (100 M) for Trpv1 and Trpm8 to confirm the functional expression of these two channels in iSG neurons (20, 21). KCl (100 mM) was transiently perfused to monitor the functional viability of the cells at the beginning and end of recording. Only cells that showed responses to KCl were chosen for analysis. Nearly all the iSG clusters induced by ABI showed green fluorescence following incubation with the calcium indicator Fluo-8 AM (Fig. 3, L to N). We found that among all the recorded cells, 56.8% of them (25 of 44) responded to capsaicin and 70.4% (19 of 27) to menthol (Fig. 3, O to U), suggesting that a large number of iSG neurons express ion channels characteristic of nociceptive sensory neurons.

We investigated the ability of iSG neurons to survive and integrate in the DRG by microinjecting dissociated iSG neurons reprogrammed from CAG-GFP mouse embryos (28), into adult rat DRG explants (fig. S4A). Following 2 weeks of culture of the transplanted explants, we found that the GFP+ iSG neurons survived, spread, and integrated in the DRG and were immunoreactive for the pan-sensory neuron marker HuC/D (fig. S4B). Moreover, a large fraction of them were immunoreactive for TrkA, while a small portion expressed TrkB or TrkC (fig. S4, C to E), indicating that iSG neurons maintain subtype specificity in the DRG.

Consistent with their sensory neuron identity, after a week in culture, iSG neurons reprogrammed from Tau-GFP mouse embryos (30) spontaneously aggregated with rhodamine-labeled sensory neurons dissociated from E13.5 mouse DRGs to form DRG-like organoids interconnected by nerve fibers (fig. S4, N to Q). In contrast, when GFP+ iSG neurons were cocultured with P0 mouse skin cells, they did not co-aggregate with skin cells; instead, they projected to and innervated vimentin-immunoreactive epidermal cells with multiple terminal nerve endings (fig. S4, J to M), in agreement with the fact that DRG neurons normally innervate their peripheral targets in the epidermis.

Previous studies have demonstrated that peripheral SG neurons and RGCs share many common molecular hallmarks, making it difficult to distinguish these two types of sensory neurons in cell culture. During the past decade in stem cell research, a number of supposedly specific molecular markers have been used to identify differentiated or induced SG neurons and RGCs (2225); unfortunately, however, no efforts have been made to confirm the specificity of these markers, casting doubt on some of the previous conclusions. Because Brn3a, Brn3b, and Isl1 are TFs crucial for retinal cell development, in particular, RGC development (13, 14, 16), there is a possibility that they may also be able to reprogram MEFs into RGCs. We thus set out to identify molecular markers that can definitively distinguish RGCs from peripheral sensory neurons. We postulated that such unique identifiers could be single-molecule markers or a combination of multiple-molecule markers that must be present only in RGCs within the retina but not in peripheral sensory neurons or any other tissues.

In the mammalian retina, our early studies have identified Brn3a and Brn3b as the gold standard markers for RGCs, but meanwhile revealed their expression in peripheral SG and other CNS areas (10, 15). In the mouse, immunolabeling of retinal and DRG sections confirmed the specificity of Brn3a and Brn3b in RGCs within the retina as well as their widespread expression in DRG neurons (fig. S5A), indicating that Brn3a and Brn3b alone cannot distinguish RGCs from DRG neurons outside the retina. Similarly, many other commonly used RGC markers including Thy1.2, RPF-1, Rbpms, HuC/D, Six6, Ebf, Isl1, Zeb2, Lmo4, Ldb1, and Sncg all displayed expression in the DRG (fig. S5A). Expressed in both RGCs and DRGs were also a number of sensory neuron markers including CGRP, peripherin, vGLUT2, vGLUT3, GABA, TrkA, TrkB, TrkC, and P2X3 (fig. S5A). Pax6 appeared to be the only exception among all the tested markers, which is expressed in RGCs and inner nuclear layer within the retina but absent from DRG (fig. S5A). Given the expression of Brn3a, Brn3b, Thy1.2, RPF-1, and Rbpms only in RGCs within the retina, a combination of Pax6 with any of these proteins could serve as a potential unique identifier for RGCs.

The uniqueness of double-positive markers was tested by immunolabeling sections of other CNS areas. Double-immunostaining showed that neuronal cells immunoreactive for both Pax6 and RPF-1, Thy1.2, Rbpms, HuC/D, or Tuj1, albeit absent from the DRG, were present not only in the retina but also in the spinal cord (Fig. 4A), precluding their use as specific RGC markers. The Isl1+Pax6+ double-positive cells were absent from the DRG and spinal cord but present within both the ganglion cell layer and inner nuclear layer in the retina (Fig. 4A), precluding also this combination as a specific RGC identifier. By contrast, Brn3a+Pax6+ and Brn3b+Pax6+ double-positive cells were exclusively RGCs in the retina and were not found in the DRG or spinal cord (Fig. 4A). Given the detection of Brn3a/Brn3b expression in the midbrain and cerebellum (10, 15), we investigated whether there were Brn3a+Pax6+ and Brn3b+Pax6+ double-positive cells in these two brain regions and found none at stages E13.5, P4, and P21 (Fig. 4A). Thus, these results together demonstrate that a combination of Pax6 and Brn3a or Brn3b double markers can serve as specific identifiers for RGCs.

(A) Cryosections from the indicated regions and stages of mice were stained by double immunofluorescence with the indicated antibodies and counterstained with nuclear DAPI. Arrows point to representative double-positive cells. GCL, ganglion cell layer; INBL, inner neuroblastic layer; INL, inner nuclear layer; IPL, inner plexiform layer; ONBL, outer neuroblastic layer; ONL, outer nuclear layer; OPL, outer plexiform layer. Scale bars, 40 m. (B to E) MEFs were infected with the ABI lentiviruses, cultured for 14 days, and double-immunostained with the indicated antibodies and counterstained with nuclear DAPI. Arrowheads in (D) indicate colocalized cells in the outlined region located outside the iSG. Scale bars, 40 m (B and C) and 20 m (D and E). (F to I) MEFs infected with the ABI lentiviruses and cultured for 14 days were dissociated and double-immunostained with anti-Brn3a and anti-Pax6 antibodies and counterstained with nuclear DAPI. Arrows indicate colocalized cells. Scale bars, 20 m. (J) qRT-PCR analysis of expression levels of the indicated genes (ex, exogenous; en, endogenous) in MEFs infected with ABI or GFP viruses (means SD, n = 3 or 4). *P < 0.05, **P < 0.001, ***P < 0.0001. (K and L) Quantification of DAPI- or Tuj1-positive cells that express Brn3a or Pax6 in MEFs infected with the ABI viruses (means SD, n = 4). (M) Quantification of Brn3a+Pax6+ iRGCs induced by ABI (means SD, n = 4).

We used the single-cell RNA sequencing (scRNA-seq) technology to further confirm the specificity of Brn3a+Pax6+ and Brn3b+Pax6+ double-positive markers. A Brn3b-GFP knockin mouse line was generated, and RGCs were enriched and sequenced by scRNA-seq. In addition, we isolated adult mouse DRG cells, which were then similarly sequenced. Clustering and expression analyses of the sequenced RGCs revealed that most of them expressed Pax6, Brn3a, or Brn3b and both Pax6 and Brn3a or Brn3b; in particular, the great majority of RGCs were positive for both Pax6 and Brn3a (fig. S5B). By contrast, there was a complete absence of DRG cells expressing both Pax6 and Brn3a or Brn3b, although Brn3a and Brn3b were present in most DRG cells (fig. S5B), consistent with the idea that a combination of Pax6 and Brn3a or Brn3b double markers can be used to distinguish RGCs from DRG cells.

To assess whether ABI and AI are able to induce iRGCs in addition to iSG, we immunostained ABI-reprogrammed MEF cells with antibodies against Tuj1, Brn3a, and/or Pax6. Double-labeling between Tuj1 and Brn3a or Pax6 showed that Brn3a-expressing cells were concentrated in the iSG, whereas the great majority of Pax6-expressing cells were distributed outside of the iSG and only few of them were seen in the iSG (Fig. 4, B and C). Moreover, all Pax6-positive cells coexpressed Brn3a and most of them displayed relatively weak Brn3a expression (Fig. 4, D and F to I), indicating that iRGCs were reprogrammed from MEFs by ABI. Similar to the distribution of endogenous RGCs that are spread throughout the RGC layer, the Brn3a+Pax6+ iRGCs were scattered and did not organize into clustered mini-ganglia (Fig. 4, C and D), unlike the induced peripheral SG neurons. Quantification of immunoreactive cells indicated that approximately 21.1% of all cells were induced by ABI into Brn3a+ neurons, whereas only about 2.6% of them were reprogrammed into Pax6+ cells (Fig. 4K). Furthermore, there were 93.1% of Tuj1+ cells coexpressing Brn3a, 10.5% of Tuj1+ cells coexpressing Pax6, and 12.6% Brn3a+ cells coexpressing Pax6 (Fig. 4, L and M), suggesting that only a small fraction of the ABI-reprogrammed neurons are Brn3a+Pax6+ double-positive iRGCs and that most of them are Brn3a+ iSG neurons. Similarly, a small number of Brn3a+Pax6+ iRGCs were induced by AI (fig. S3, T and U).

In agreement with the induction of a small proportion of iRGCs by ABI, immunostaining showed that some cells outside the iSG were positive for Thy1.2 (Fig. 4E). qRT-PCR assays revealed a significant up-regulation of several commonly used RGC marker genes including the endogenous Brn3b, Brn3a, RPF-1, Pax6, Sncg, HuC, and HuD in MEFs infected with ABI lentiviruses compared to those infected with GFP viruses (Fig. 4J), consistent with the induction of iRGCs by ABI from MEFs. Moreover, during the time course of ABI reprogramming, we were able to show by qRT-PCR assay that Pax6 expression was progressively induced starting from day 9 (fig. S1E).

We further characterized the iSG neurons and iRGCs by bulk and single-cell transcriptome profiling. First, we carried out bulk RNA-seq analysis of ABI- and GFP-transduced MEFs after 2 weeks of induction (Fig. 5A). Scatter plot and hierarchical cluster analyses showed that there were numerous genes whose expression was down-regulated or up-regulated in ABI-transduced compared to GFP-transduced MEFs (fig. S6, A to C, and table S1). We performed gene set enrichment analysis (GSEA) of the altered genes followed by network visualization (31), and one major group of clustered networks emerged (fig. S6D). This group encompasses only up-regulated genes that are enriched for GO (gene ontology) terms relevant to neural function and development such as synaptic signaling, synaptic vesicle, synapse organization, neurotransmitter transport, regulation of neurotransmitter levels, exocytosis, calcium ion binding, ligand-gated channel activity, neuron projection, axon, and nervous system development. These results are consistent with the induction of functional SG and retinal ganglion neurons by ABI from MEFs. In agreement with this and qRT-PCR assays (Figs. 2, W and X, and 4J), bulk RNA-seq confirmed up-regulation of many SG and retinal ganglion genes in ABI-transduced MEFs, including NF200, Brn3a, TrkB, vGlut3, Trpv1, P2X3, Gria1, Pax6, Sox11, Sncg, and Thy1 (fig. S6, E and F).

(A) Schematic illustration of the processes for bulk RNA-seq and scRNA-seq analyses. (B) t-distributed Stochastic Neighbor Embedding (t-SNE) plot of the 15 cell clusters generated from the sequenced single iSG neurons. (C to J) t-SNE plots colored by expression of the indicated conventional SG marker genes. (K) Violin plots showing expression patterns of the indicated conventional SG marker genes in single-cell clusters.

We separated ABI-induced iSG from MEFs by mild dissociation and filtering and then carried out scRNA-seq analysis of single iSG cells using the 10 Genomics Chromium platform (Fig. 5A) (32). After processing the sequencing data by the Cell Ranger software pipeline, we clustered the 3231 sequenced single cells into 15 clusters using the Seurat software package (Fig. 5B), which is an R toolkit for single-cell genomics (33). Investigation of gene expression patterns showed high levels of expression of general neuronal marker genes such as Tuj1, Tau, and Map2 in clusters 1, 3, 5, 8, and 11, whereas they are expressed much more weakly in the rest of the clusters (fig. S7, A and C to E). By contrast, many of the previously identified MEF marker genes (34) including Klf4, Mmp2, and Postn have, in general, an opposite expression pattern, displaying little expression in clusters 1, 3, 5, 8, and 11 but obvious expression in the rest of the clusters (fig. S7, A and F to H). Pseudotime trajectory of the sequenced cells constructed using Monocle (35) yielded three presumptive states along which Klf4 expression progressively decreases, while the expression of Tuj1, Tau, and Map2 progressively increases (fig. S7, I and J). Thus, in iSG induced from MEFs by ABI for 2 weeks, there are still some cells that express both neuronal and MEF markers, suggesting that MEFs undergo a transitional intermediate stage that exhibits both MEF and neuronal characteristics before completely reprogrammed into mature iSG neurons (fig. S7B). Consistent with this idea, there were many cells coexpressing both Tuj1 and the fibroblast marker gene vimentin in a number of the clusters (fig. S7K). By days 6 to 12 of ABI reprogramming, we also detected by immunolabeling some cells and nerve bundles that were immunoreactive for both Tuj1 and vimentin proteins (fig. S7L).

Consistent with the induction of iSG neurons, there is expression of NF200, peripherin, p75NTR, TrkB, TrkC, Trpv1, Trpv2, P2X3, Accn2, Kcnq2, Cacna1a, and CGRP in various clusters of sequenced iSG cells (Fig. 5, C to K). In particular, NF200, P2X3, Accn2, Kcnq2, and Cacna1a are primarily expressed in clusters 1, 3, 5, 8, and 11, and peripherin, Trpv1, and Trpv2 are mainly present in a small number of cells in clusters 1, 3, and 5 (Fig. 5, C, D, F to I, and K), indicating their expression in mature iSG neurons and their expression specificity. Many genes that are markers for both SG neurons and RGCs, such as Thy1, Sncg, Rbpms, Gap43, HuC, Sox11, Sox12, Zeb2, Brn3a, Brn3c, and RPF-1, are also expressed in various clusters of sequenced iSG cells (Fig. 6). However, the RGC marker Pax6 is only enriched in small cell clusters 12 and 13 and expressed in few cells in other clusters, consistent with the observation that only a very small number of iSG cells were immunoreactive for Pax6 (Figs. 4C and 6I). The Pax6+ cells in clusters 12 and 13 do not appear to be iRGCs because they lack expression of RGC markers Brn3a, Brn3c, and RPF-1 (Fig. 6I). In agreement with the observation that iRGCs were scattered and rarely present in iSG, there are only a small number of cells coexpressing both Pax6 and Tuj1, Thy1, Gap43, HuC, Sox11, Brn3a, or RPF-1, primarily in clusters 5 and 6 (Fig. 4C and fig. S8, A to H).

(A to H) t-SNE plots colored by expression of the indicated conventional RGC marker genes. (I) Violin plots showing expression patterns of the indicated conventional RGC marker genes in single-cell clusters.

We reprogrammed human skin fibroblasts (HSFs) into iSG with a mixture of the three individual ABI lentiviruses only at a low efficiency. To increase the reprogramming efficiency, we created a Dox-inducible lentiviral construct containing Ascl1, Isl1, and Brn3b in a single open reading frame (ORF) tethered by the P2A and T2A self-cleaving peptide sequences (Fig. 7A). HSFs infected by these single ABI-expressing viruses readily formed well-networked iSG in approximately 45 days in the neural differentiation medium (Fig. 7B). Immunostaining of these iSG showed that they contained typical sensory neurons expressing TUJ1, MAP2, NF200, PERIPHERIN, SYNAPSIN, VGLUT1, TRKA, TRKB, TH, and BRN3A (Fig. 7, C to K). Moreover, similar to MEFs, a small number of iRGCs were induced from HSFs by ABI that were immunoreactive for both PAX6 and BRN3A (Fig. 7, L and M). qRT-PCR assays showed that TUJ1 expression was gradually induced by ABI starting from day 10 but the more mature neuron marker gene MAP2 was not induced until day 20 (Fig. 7N). In contrast, the fibroblast marker genes COL1A1 and TWIST2 were progressively down-regulated starting from day 10 (Fig. 7O), concurrent with TUJ1 induction.

(A) Schematic of the lentiviral construct. (B to M) Networked iSG induced by ABI from HSFs (B) and iSG and iRGCs double-immunostained with the indicated antibodies and counterstained with DAPI (C to M). (N to Q) qRT-PCR assay showing the time course [days 1 (D1) to 20 (D20)] of expression changes of the indicated marker genes in HSFs infected with ABI or GFP viruses (means SD, n = 4). *P < 0.0001 for (N), (P), and (Q) and *P < 0.01, **P < 0.001, ***P < 0.0001 for (O). hES, human embryonic stem cell; hiNSC, human neural stem cell. (R) Schematic of EdU labeling schedule. (S to U) ABI-transduced HSFs were labeled by EdU for 29 days and colabeled for both TUJ1 and EdU before (S) and after dissociation (T). (U) Corresponding quantification (means SD, n = 4). *P < 0.0001. (V to X) ABI-transduced HSFs were labeled by EdU for 24 hours and colabeled for both TUJ1 and EdU before (V) and after dissociation (W). (X) Corresponding quantification (means SD, n = 4). *P < 0.0001. (Y, Z, and A) Current-clamp recordings revealed single action potential responses (single-spiking) of a differentiated iSG neuron (Y). Voltage-clamp recordings of the same neuron indicated fast activated and inactivated inward sodium currents as well as outward potassium currents (Z and A). The sodium currents of the iSG neuron were effectively blocked by TTX and were partially restored by its washout (A). (B and C) Current-clamp recordings revealed an iSG neuron with multiple action potential responses (multiple-spiking). (D) Spontaneous postsynaptic currents recorded from a differentiated iSG neuron. Scale bars, 80 m (B) and 20 m (C to M, S, T, V, and W).

To determine whether iSG induction was mediated by a pluripotent or neural progenitor intermediate, we investigated by qRT-PCR assay expression of pluripotent factor genes and neural progenitor marker genes during HSF reprogramming by ABI. We found no significant change in expression levels of pluripotent factor genes OCT4, KLF4, and NANOG during the reprogramming process (from day 1 to day 20) (Fig. 7P). Similarly, there was no induction of NESTIN and OLIG2 expression in the reprogramming process (Fig. 7Q), suggesting that iSGs were reprogrammed from HSFs by ABI without an intermediate state of pluripotent or neural progenitors. Consistent with this, by day 30 of reprogramming, almost no reprogrammed TUJ1+ neurons were labeled by EdU when EdU was added to the reprogramming cell culture for 29 days or 24 hours (Fig. 7, R to X), confirming that iSG reprogramming occurred in the absence of an intermediate state of proliferative progenitors.

The electrophysiological properties of reprogrammed human iSG neurons were evaluated by whole-cell patch-clamp recording. At day 60, most neurons (15 of 17) exhibited typical sodium and potassium currents and showed action potential responses (Fig. 7, Y, Z, and A). In addition, the inward sodium current could be specifically and completely blocked by TTX and partially recovered by its removal (Fig. 7A). Similar to mouse iSG neurons, some (4 of 17) were multi-spiking, while the others (11 of 17) were single-spiking (Fig. 7, Y, B, and C), although in human iSG single-spiking neurons appeared to be more abundant than those in mouse iSG (Fig. 3K). Among all neurons recorded from day 25 to day 39, a small fraction (4 of 44) displayed spontaneous postsynaptic activities (Fig. 7D), indicating the ability for human iSG neurons to form functional synapses, in agreement with their synapsin labeling (Fig. 7F). Thus, the human iSG neurons induced by ABI from HSFs have the physiological properties characteristic of mature neurons.

We further investigated the ability of human iSG neurons to survive and integrate in the DRG by microinjecting GFP-tagged human iSG neurons into adult rat DRG explants (fig. S4A). Two weeks after transplantation, we found that the GFP+ neurons survived and integrated in the DRG, and were all (99 of 99) immunolabeled by an anti-human nuclei antibody (fig. S4F), indicating that material transfer did not occur between the transplanted and host cells. The transplanted GFP+ cells were immunoreactive for pan-sensory neuron markers, and some of them were immunoreactive for TrkA, TrkB, or TrkC (fig. S4, G to I), suggesting that similar to mouse iSG neurons, transplanted human iSG neurons can also survive in the DRG and maintain sensory neuron subtypes.

Although scattered sensory neurons (iSNs) were previously induced from fibroblasts by TFs (20, 21), to our knowledge, this is the first time to demonstrate that self-organized iSG organoids can be consistently induced directly from somatic cells by defined TFs. The bHLH TF Ascl1 has been shown to be a pioneer neurogenic TF in converting fibroblasts into neurons in in vitro somatic cell reprogramming (26). However, the neurons reprogrammed by Ascl1 alone are mostly slow-maturing and excitatory (36). Addition of Brn2 and Myt1l (BAM) improved the reprogramming efficiency, maturing speed, and varieties of the iNs (27, 36, 37). The iNs induced by BAM were rather generic but motor neurons could be specifically induced when BAM were combined with four other TFs (Lhx3, Hb9, Isl1, and Ngn2) (38). Similarly, when trying BAM with other combinations, Wainger et al. (20) found that the combination of five factors (Ascl1, Myt1l, Ngn1, Isl2, and Klf7) could successfully convert fibroblasts into nociceptor neurons. Notably, all of these reprogramming formulas include Ascl1 as a key component. Alternatively, the bHLH TFs Ngn1 and Ngn2 were combined with Brn3a to reprogram fibroblasts into mature iSNs (21).

Our experiments in this study have demonstrated that the ABI TF combination is most effective in inducing MEFs into self-organized mini-SG, while the AI and AB combinations have a weaker activity (fig. S8J). Thus, Brn3a/3b appears to act synergistically with Isl1 to improve the induction efficiency of iSG organoids. As revealed by time-lapse microscopy, the larger iSG organoids are formed by cell migration and coalescing smaller cell aggregates. The mini-SG induced from both murine and human fibroblasts contain mature and functional sensory neurons. They exhibit typical inward sodium currents, which can be blocked by TTX and recover after TTX removal, and are a mixture of neurons displaying multiple-spiking action potentials or single-spiking action potential. They also show calcium responses to potassium chloride, capsaicin, and menthol. All these features closely resemble their endogenous counterparts.

The iSG neurons reprogrammed by ABI display extensive cell diversities in their expression of characteristic receptors, ligands, ion channels, neuropeptides, neurotransmitters, and so on, similar to the endogenous sensory neurons. In agreement with iSNs induced by Ngn1/2 and Brn3a (21), the iSGs contain roughly equivalent percentages (~30%) of TrkA+, TrkB+, and TrkC+ neurons, supporting the notion that Trk receptors may arise in a stochastic manner such that each donor cell has an approximately equivalent chance to express one of the Trk receptor genes. By bulk RNA-seq, scRNA-seq, and/or qRT-PCR analyses, we investigated the characteristic markers involved in sensory signaling pathways including transduction, conduction, and synaptic transmission of sensory signals. At the transduction level, we found up-regulated expression of genes responsible for perceptions to stimuli such as heat (Trpv1, Trpv2, Trpv3), cold (Trpa1), damage (P2X3, Bdkrb1), and touch (Trpc1, Trpc4, Asic2/Accn1, Accn2). Trpv1, also known as capsaicin receptor that is expressed mainly in the nociceptive neurons (29), has been shown to be present and functional in iSG neurons by capsaicin stimulation. The signaling conduction of sensory neurons is primarily mediated by sodium channels, which propagate the signals, and potassium channels, which usually act to reduce excitability. We found that the expression of many Na+ channels (Scn1a, 2a1, 2b, 3a, 3b, 7a, 11a) and K+ channels (Kcnq2, 4; Kcna2, 3, 4, 5, 6; Kcnb2, c1, d2, e4, f1, h2, j2, k3, s3, t1, etc.) were up-regulated in iSG neurons. For synaptic transmission, neurotransmitter receptors and presynaptic voltage-gated Ca2+ channels are two groups of important regulatory molecules. Correspondingly, the expression of a variety of neurotransmitter receptors (Nk1r, Nr3c2; Gria1, 2, 4; Grid1, k1, k2, k4, k5; Grin1, 2a, etc.) and Ca2+ channels (Cacna1a, 1b, 1d, 2d1, 2d2, 2d3; Cacnb1, g4, etc.) were significantly up-regulated in iSG neurons.

Apart from the molecular and electrophysiological properties, ABI-reprogrammed iSG neurons also have salient cellular and innervation characteristics of sensory neurons. For instance, when transplanted, they can survive, integrate, and maintain the nociceptive, mechanoreceptive, and proprioceptive subtypes in the DRG. Moreover, the iSG neurons exhibit strong affinity for endogenous DRG neurons and spontaneously aggregate with them to form interconnected DRG-like organoids in culture. In addition, we have demonstrated by coculture that the iSG neurons have the capacity to innervate the peripheral targets of sensory neurons, i.e., epidermal cells, indicating that the iSGs contain bona fide sensory neurons reprogrammed from fibroblasts by ABI.

Therefore, the combination of ABI TFs is able to reprogram murine and human fibroblasts into self-organized iSG organoids composed of heterogeneous sensory neurons, closely resembling the endogenous SG. Previously, Ascl1 in combination with Brn3a, Brn3b, or Brn3c was shown to induce iNs from MEFs (39). Although the sensory neuron identity of the iNs was not investigated, some of the data suggest the formation of iSG organoids by the Ascl1 and Brn3a combination (39). This is consistent with our work that showed that the AB combination enabled induction of iSG organoids, albeit fewer than those induced by the ABI combination (Fig. 1). Similarly, the data reported in a previous study also suggest the formation of iSG organoids by the nociceptive neurons reprogrammed from MEFs using a 5-TF combination (20). However, unlike the ABI combination, the 5-TF combination did not appear to induce iSG organoids from human fibroblasts (20), suggesting a difference in reprogramming capacity and/or efficiency by different combinations of TFs.

The peripheral ganglia, including cranial ganglia, DRG, trigeminal ganglia, enteric system ganglia, autonomic ganglia, and others, are derived from migrating NC cells. The NC is thought to be a unique cell population found in vertebrates and is initially induced at the neural plate border as a result of neural plate folding and fusion (40). After undergoing an epithelial-to-mesenchymal transition, the NC cells delaminate from the neuroepithelium and become highly migratory. Most NC cells migrate as a chain or group in a so-called collective cell migration, in which cell contact and cooperation allow them to migrate directionally. Guided by local cues and long-range chemoattractants, NC cells reach their destination and differentiate into ganglia and other tissue types.

Mutations in crucial genes controlling the migration and differentiation of NC cells may cause aganglionosis such as Hirschsprungs disease, which may occur by itself or in association with other genetic disorders such as Down syndrome, Waardenburg-Shah syndrome, Mowat-Wilson syndrome, or Bardet-Biedl syndrome (41). This group of genes includes RET, ZEB2, EDNRB, SOX10, and PHOX2B, and mutations of them or their regulatory sequences may increase the risk of Hirschsprungs disease more than 1000-fold (41). In our RNA-seq data, the expression of Ret, Zeb2, Ednrb, and Sox10 was significantly up-regulated in the iSG neurons, in agreement with their importance in the differentiation and formation of SG. Other known risk genesBbs4, Bbs10, Edn3, Gfra1, and Arvcf (41)were also significantly elevated in iSG. The hereditary sensory and autonomic neuropathies (HSANs) consist of several clinically heterogeneous disorders characterized by defective development and maintenance, and progressive degeneration of sensory and autonomic nervous systems. Mutations in the SPTLC1, WNK1, IKBKAP, and TRKA genes have been shown to cause HSAN types I to IV, respectively (42). In addition, loss-of-function mutations in SCN9A and PRDM12 result in congenital insensitivity to pain (6, 43). Indifference to pain appears to be desirable but risks the loss of a vital protective mechanism with dangerous consequences such as unknowingly chewing tongues and lips and damaging digits and joints. On the other hand, pain hypersensitivity reduces the quality of life and may increase susceptibility to chronic pain.

The ability to reprogram somatic cells into iSG organoids by ABI presents new possibilities for modeling sensorineural diseases, studying their pathogenesis, screening for counteractive drugs, and developing cell replacement therapies. For example, patient-derived iSG organoids may be used as an in vitro model for pain to screen and evaluate potential drug treatments. In the future, iSG organoids and neurons may also be used in transplantation as a cell replacement therapy for damaged or degenerated SG. In this respect, we found that transplanted iSG neurons were able to integrate and maintain the nociceptive, mechanoreceptive, and proprioceptive subtypes in the DRG. It has long been recognized that genetic factors are a major contributor to personalized pain perception and the efficacy of analgesic drugs (29). Generation of iSG organoids from autologous somatic cells may thus provide an exciting novel approach to model personalized pain and sensory pathology and help to achieve precision medicine for pain.

In this study, we made efforts to define specific molecular markers to identify RGCs both in vitro and in vivo. This is important because it is impossible to apply commonly used RGC markers to distinguish RGCs from SG neurons in vitro given the high molecular similarity between these two cell types. Since the 1990s, we have established the Brn3 family of TFs, Brn3a, Brn3b, and Brn3c, as the gold standards to identify RGCs in the retina (10, 15). However, Brn3 proteins are not unique to the retina but expressed in other sensory and CNS tissues as well, e.g., trigeminal ganglia, DRG, spiral ganglia, and midbrain (10, 15, 44). Apart from Brn3 proteins, Thy1.2, Sncg, and Rbpms are also commonly used as specific RGC markers. But here again, we show their abundant expression in DRG neurons. Therefore, although because of the spatial separation of the retina from SG in the organism, these so called RGC-specific markers are able to distinguish RGCs from SG neurons in vivo, they are unable to do so in vitro. Unfortunately, however, a number of previous studies used these supposedly RGC-specific markers to identify RGCs induced from ESCs, iPSCs, and somatic cells in vitro (2225), casting doubt on some of the arrived conclusions.

To avoid misidentifying iRGCs and iSG neurons in vitro, we screened for molecular markers that can definitively distinguish RGCs from SG neurons. A rigorous criterion was set that these unique identifiers should be single-molecule markers or a combination of multiple-molecule markers that must be present only in RGCs within the retina but not in SGs or any other tissues. Following a careful examination of a large number of known RGC and SG neuron markers, it became apparent that none of them alone were specific to RGCs. Further double-immunolabeling analysis indicated that a combination of Pax6 and Brn3a or Brn3b double markers satisfied the criterion of specific RGC identifiers. Brn3a+Pax6+ and Brn3b+Pax6+ double-positive cells were found exclusively in RGCs of the retina but not in the DRG, spinal cord, midbrain, or cerebellum, where Brn3a, Brn3b, or Pax6 is normally expressed. Moreover, scRNA-seq analysis confirmed Brn3a+Pax6+ and Brn3b+Pax6+ cells as RGCs and their complete absence in the DRG. Thus, we are able to define the combination of Pax6 with either Brn3a or Brn3b double protein markers as specific identifiers for RGCs. Armed with this knowledge, we found that ABI TFs had the capacity to reprogram MEFs into a small number of Brn3a+Pax6+ iRGCs, representing about 13% of all Brn3a+ neurons. Unlike iSG organoids resembling endogenous SG, iRGCs did not coalesce into clusters but remained scattered, similar to the dispersive distribution pattern of endogenous RGCs in the retina (fig. S8, I and J). Therefore, ABI-induced iSG and iRGCs maintain the morphology characteristic of their endogenous equivalents.

In summary, in a screen of multiple SG and RGC TFs, we have identified a triple-factor combination ABI as the most efficient combination to reprogram self-organized and networked iSG organoids from mouse and human fibroblasts. By immunostaining, qRT-PCR, whole-cell patch-clamp recording, calcium imaging, and bulk and scRNA-seq approaches, we are able to demonstrate that the iSG organoids display molecular and cellular features, subtype diversity, electrophysiological properties, and peripheral innervation patterns characteristic of peripheral SGs. Furthermore, using immunolabeling and scRNA-seq analyses, we have identified bona fide RGC-specific molecular markers to demonstrate that the ABI combination has the additional capacity to induce from fibroblasts a small number of iRGCs. Unlike the ABI-reprogrammed iSG organoids characteristic of endogenous SG, iRGCs maintain a dispersive distribution pattern resembling that of endogenous RGCs in the retina. The iSG organoids and iRGCs may be used to model sensorineural/retinal diseases, to screen for effective drugs and potentially, as cell-based replacement therapy.

All experiments on rodents were performed according to the IACUC (Institutional Animal Care and Use Committee) standards and approved by Sun Yat-sen University and Zhongshan Ophthalmic Center. The C57BL/6 mice were purchased from the Vital River Laboratories (Beijing, China).

The full-length ORFs of Brn3a, Brn3b, Isl1, Math5, Ebf1, Pax6, Tfap2a, Nr4a2, Nrl, Crx, Ptf1a, Neurod1, Lhx2, Ngn1, Ngn2, Chx10, Sox2, Rx, Meis1, Foxn4, Otx2, Sox9, or Six3 were subcloned into the Eco RI site of the FUW-TetO vector (45). In addition, by overlapping PCR subcloning, Ascl1, Isl1, and Brn3b were tethered by P2A and T2A self-cleaving peptide sequences into a single ORF, which was inserted into the same FUW-TetO backbone. Lentiviruses were prepared as previously described (34).

The MEFs were prepared as previously described (34). For isolation of mouse epidermal cells, P0 C57BL/6 mice were anesthetized with ice for 5 min and the brain was removed using a sterilizing razor in a 10-cm culture dish containing Hanks balanced salt solution (HBSS) (Gibco). The epidermis was isolated from the remaining tissue using a pair of fine-tip forceps under a dissection microscope, transferred into a fresh 6-cm culture plate containing 1 ml of 0.25% trypsin, thoroughly minced using a pair of surgical scissors and forceps, and incubated for 15 min at 37C in a CO2 incubator. Six-milliliter MEF medium containing Dulbeccos modified Eagles medium (DMEM)/High Glucose (HyClone) supplemented with 10% fetal bovine serum (Gibco), 1 penicillin/streptomycin (Gibco), 1 MEM nonessential amino acids (NEAA) (Gibco), and 0.008% (v/v) 2-mercaptoethanol (Sigma-Aldrich) was added into the plate to terminate the reaction. After being mixed using a 10-ml pipette, the digested tissue was transferred to a 15-ml fresh tube, centrifuged at 1000 rpm for 5 min, and resuspended in 5-ml fresh MEF medium. The isolated epidermal cells were expanded by culture in the MEF medium at 37C in a CO2 incubator. The HSFs were purchased from the American Type Culture Collection (CRL1502, 12-week gestation). MEFs, mouse epidermal cells, and HSFs were all maintained and expanded in the MEF medium.

To induce iSG and iRGCs from MEFs, 3 104 MEF cells (at passage 3) were cultured in 500-l MEF medium in a well of a 24-well plate containing a glass coverslip precoated with Matrigel (Corning). They were infected the next day with 500-l mixture of lentiviruses and fresh MEF medium in the presence of polybrene (10 g/ml). After 16-hour infection, the virus and medium mixture was removed. The cells were induced for 4 days in the neuron basic medium [(DMEM/F12 (1:1) (Life Technologies) supplemented with 1 B27 (Gibco) and basic fibroblast growth factor (bFGF) (10 ng/ml) (R&D Systems)] in the presence of Dox (2 ng/ml) (Sigma-Aldrich) and then for another 4 days in the neuron maintenance medium containing the neuron basic medium supplemented with insulin-like growth factor 1 (IGF-1) (100 ng/ml), brain-derived neurotrophic factor (BDNF) (10 ng/ml), and glial cell linederived neurotrophic factor (GDNF) (10 ng/ml) in the presence of Dox (2 g/ml). The medium was replaced with the neuron maintenance medium without Dox following the 8-day induction period. By 14 days after infection with Ascl1, Brn3b/3a, and Isl1 (ABI), Ascl1 and Brn3b/3a (AB), or Ascl1 and Isl1 (AI) lentiviruses, many visible neuronal clusters were formed.

With modifications, the HSFs were similarly induced. In brief, after virus infection, the human cells were cultured in the neuron basic medium with Dox for 10 days and then in the neuron maintenance medium without Dox for another 10 days. On day 21, the medium was replaced with the neuron mature medium, which is the maintenance medium supplemented with NGF (20 ng/ml), NT-3 (20 ng/ml), and 10 M forskolin. Thirty days after viral infection, many neuronal clusters were visible, which were usually smaller than those induced from MEFs. To improve the induction efficiency of the HSFs, we created a Dox-inducible lentiviral construct containing Ascl1, Isl1, and Brn3b in a single ORF as described above.

RNA extraction and qRT-PCR analysis were carried out as previously described (34). The qRT-PCR primers used are shown in table S2.

Immunostaining of tissue sections and cells was carried out as previously described (34, 46). The following antibodies (with dilution information) were used: mouse anti-Brn3a (Santa Cruz Biotechnology, sc-390780; 1:1000), mouse anti-Brn3a (Santa Cruz Biotechnology, sc-8429; 1:100), goat anti-Brn3b (Santa Cruz Biotechnology, sc-6026; 1:1000), rat anti-Thy1.2 (BD Biosciences, 550543), goat antiRPF-1 (Santa Cruz Biotechnology, sc-104627; 1:100), rabbit anti-Rbpms (PhosphoSolutions, 1830-RBPMS; 1:500), mouse anti-HuC&D (Life Technologies, A-21271; 1:500), rabbit anti-Pax6 (BioLegend, 901301; 1:2000), mouse anti-Pax6 (Developmental Studies Hybridoma Bank, Pax6; 1:1000), rabbit anti-Six6 (Sigma-Aldrich, HPA001403; 1:500), rabbit anti-Ebf (Santa Cruz Biotechnology, sc-33552; 1:1000), mouse anti-Isl1 (Abcam, ab20670; 1:2000), rabbit anti-Zeb2 (Santa Cruz Biotechnology, sc-48789; 1:1000), rat anti-Lmo4 (1:1000; (47), rabbit anti-Ldb1 (Abcam, ab96799; 1:1000), rabbit anti-Sncg (GeneTex, GTX110483; 1:200), rabbit anti-CGRP (Neuromics, RA24112; 1:200), rabbit anti-peripherin (Millipore, ab1530; 1:1000), rabbit anti-vGLUT1 (Synaptic System,135303; 1:500), mouse anti-vGLUT2 (Abcam, ab79157; 1:500), mouse anti-vGLUT3 (Sigma-Aldrich, SAB5200312; 1:500), rabbit anti-GABA (Sigma-Aldrich, A-2052; 1:1000), goat anti-TrkA (Abcam, ab76291; 1:500), rabbit anti-TrkA (Abcam, ab76291; 1:500), goat anti-TrkB (R&D Systems, AF1494; 1:500), goat anti-TrkC (R&D Systems, AF1404; 1:500), rabbit anti-P2X3 (Millipore, AB5895; 1:100), mouse anti-Tuj1 (Millipore, MAB5564; 1:500), rabbit anti-Tuj1 (Abcam, ab18207; 1:2000), mouse anti-Map2 (Sigma-Aldrich, M1406; 1:2000), rabbit anti-synapsin (Calbiochem, 574778; 1:500), goat anti-Dcx (Santa Cruz Biotechnology, sc-8066; 1:500), mouse anti-NF200 (Millipore, MAB5266; 1:500), rabbit anti-TH (Protos Biotech, CA-101bTHrab; 1:1000), rabbit anti-Vamp (Synaptic System, 104203; 1:500), rabbit anti-p75NTR (Abcam, ab8874; 1:500), mouse anti-c-Ret (Sigma-Aldrich, o4886; 1:1000), goat anti-GFP (Abcam, ab6673; 1:2000), rabbit anti-GFP (MBL, 598; 1:2000), chicken anti-GFP (Abcam, ab13970; 1:2000), rabbit anti-vimentin (Abcam, ab92547; 1:2000), and mouse anti-human nuclei (Millipore, MAB1281; 1:200). The secondary antibodies used included donkey anti-rabbit, donkey anti-goat, and donkey anti-mouse Alexa 488 immunoglobulin G (IgG), Alexa 594 IgG, Alexa 546 IgG, Alexa 647 IgG, or Alexa 594 IgM (1:1000; Invitrogen). 4,6-Diamidino-2-phenylindole (DAPI) (Invitrogen) was used for nuclear counterstaining. Images were captured with a laser scanning confocal microscope (Carl Zeiss, LSM700).

One day following infection with ABI lentiviruses, the MEFs were cultured in the presence of 10 M EdU (Life Technologies) for 13 days, or 13 days after infection with AI or ABI viruses, the MEFs were cultured for 24 hours in the presence of 10 M EdU. The cells were then fixed, and EdU staining was carried out according to the manufacturers instruction (Life Technologies). For HSF reprogramming by ABI, EdU was added to the reprogramming cell culture for 29 days starting from day 1 of reprogramming or for 24 hours starting at day 29. Images were captured with a confocal microscope.

For time-lapse recording, we used the JuLI Stage (NanoEntek) with a motorized stage, computer-controlled lens change, and a built-in incubator that supplied humidified 5% CO2 at 37C for live cell recording. MEFs (5 104) derived from the CAG-GFP transgenic mice (28) were induced for 10 days by infection with the ABI lentiviruses or Ascl1 lentiviruses in a well of a 12-well plate precoated with Matrigel. The plate was then placed into the incubator of the JuLI Stage for time-lapse recording for 50 hours. A series of pictures were taken from each well of the 12-well plate in a period of 50 hours under the control of the JuLI EDIT software, which can also edit and replay these pictures in a continuous mode like a movie.

To prepare single iSG cells, MEFs were infected with the ABI (Ascl1, Brn3b, and Isl1) lentiviruses and induced for 2 weeks. Following addition of 500-l Accutase (Millipore) into a well of a 12-well plate, neuronal clusters were suspended by gently pipetting up and down several times using a 1-ml pipette and transferred into a 70-m cell strainer (Falcon) to collect neuronal clusters. Most neuronal clusters attached to the Nylon membrane of the 70-m cell strainer, which was cut from the cell strainer using a pair of scissors and placed into a low-adhesion 6-cm plate containing 4-ml neuron basic medium. To separate the neuronal clusters from the Nylon membrane, the plate was shaken left and right 10 times. The neuronal clusters were then transferred into a 15-ml tube, centrifuged at 1000 rpm for 5 min, resuspended with 1-ml Accutase, and incubated for 5 min at 37C in a CO2 incubator. The neuronal clusters were dissociated into many single cells, which were subsequently used for injection of DRG explants, qRT-PCR, and scRNA-seq analysis.

After euthanization of the rat by the asphyxiation method (CO2 inhalation), the vertebral columns were isolated from the rest of the tissue using a pair of sharp scissors and washed three times with HBSS in a 10-cm culture dish. Both sides of the vertebral columns were mounted onto a surgical mat using needles, and a double cut was made using a pair of surgical scissors to expose the ventral side of the spinal cord. After removal of the spinal cord, DRGs were exposed in the contralateral dorsal spinal roots and pulled out using a pair of fine tweezers. They were collected into a 6-cm culture dish containing HBSS after removal of the attached excessive fibers and connective tissues under a dissection microscope. Four DRGs were transferred onto a Millipore Millicell-CM Low Height Culture Plate Insert using a 3-ml Pasteur pipette, and the rest of HBSS was removed using a 200-l pipette. Then, the insert was placed into a well of a six-well plate containing 1-ml DRG culture medium [BEM (Gibco) supplemented with 20 mM glucose, 1 KIT (Gibco), putrescine (16 ng/ml) (Sigma-Aldrich), 10 mM vitamin C (Sigma-Aldrich), NGF (20 ng/ml) (PeproTech), and 10 mM 5-fluoro-2-deoxyuridine (FDU) (Sigma-Aldrich)]. After being cultured for 1 day, each DRG was injected with 4 103 GFP-labeled single iSG cells. Two weeks following iSG cell injection, the explants were processed and immunostained as described above.

Whole-cell patch-clamp recordings of the iNs were performed with the EPC 10 USB amplifier (HEKA Electronik, Lambrecht, Germany) as previously described (34). Neurons induced from MEFs for 9 or 14 days or from HSFs for 25 to 60 days were used for patch-clamp recordings. In brief, coverslips with adhered cells were transferred into a recording chamber and bathed with Ringers containing 125 mM NaCl, 2.5 mM KCl, 1 mM MgSO4, 2 mM CaCl2, 1.25 mM NaH2PO4, 26 mM NaHCO3, and 20 mM glucose, bubbled with 95% O2 and 5% CO2. Cell responses were recorded with 6- to 9-megohm resistance pipettes that were filled with an internal solution containing 105 mM K-gluconate, 5 mM KCl, 5 mM NaOH, 15 mM KOH, 0.5 mM CaCl2, 2 mM MgCl2, 5 mM EGTA, 2 mM adenosine 5-triphosphate, 0.5 mM guanosine 5-triphosphate, 10 mM Hepes, and 2 mM ascorbate (pH 7.2). The cells and recording pipettes were viewed on a monitor that was coupled to a charge-coupled device camera (Evolve, Photometrics, Tucson, USA) mounted on an upright microscope. Oxygenated external solution was continuously perfused into the recording chamber at a flow rate of 1.5 to 2 ml/min by a peristaltic pump (LEAD-2, Longer Pump, Hebei, China). Capacitive transients were compensated via the Patch Master software (PatchMaster, HEKA), and the series resistance was compensated by ~50%. For current-clamp recording, a small, constant holding current was injected to maintain resting membrane potential (Vrest) at 70 mV and current pulses with a step size of 10 pA were applied to induce action potentials. Voltage-clamp recordings were performed on the same cells directly following current clamp recordings. A simple step protocol from 90 to +30 mV for 200 ms was applied to assess the voltage-gated sodium channels and voltage-gated potassium channels. TTX (Tocris, USA) was added to the bath solution to a final concentration of 0.5 M and perfused into the recording chamber for 5 min. After recording of the currents again, TTX was washed out, followed by the third time of recording.

The fluorescent probe Fluo-8 AM (AAT Bioquest, Sunnyvale, Canada) was used to detect the changes of intracellular calcium. As described above, MEFs were induced for 2 to 3 weeks to form neuronal clusters by infection with the ABI lentiviruses. Under dark environment, glass coverslips with adhered neuronal clusters were loaded with Fluo-8 AM (10 m) for 25 to 30 min at room temperature. After three rinses with Ringers solution, the coverslip was placed into a recording chamber. An upright microscope (Olympus, BX51W1) equipped with a mercury lamp with a 488-nm filter was used to excite Fluo-8. A digital camera (Hamamatsu Photonics, Japan) that was also equipped on the microscope was used to record the fluorescent signal. The software HCImage Live (Hamamatsu Corporation, USA) was used to control the camera and ImageJ for data analysis. Following a 30-s recording of the baseline (F0), 100 mM KCl was puffed to detect the activity of the cells. After a 2-min wash with Ringers, fluorescent signals were decreased to the baseline. Then, 100 M menthol or 10 M capsaicin was puffed to stimulate the iNs. KCl (100 mM KCl) was applied again after menthol/capsaicin to confirm the viability of the tested cells. Only the cells that responded to KCl two times successively were chosen for analysis.

Bulk RNA-seq analysis was performed with modification as previously described (48). Two weeks after infection of MEFs with lentiviruses, total RNA was extracted from GFP-transduced and ABI (Ascl1, Brn3b, and Isl1)transduced MEFs using the TRIzol reagent according to the manufacturers instruction. Ribosomal RNA was depleted before preparation of RNA-seq libraries, which were subsequently sequenced using an Illumina HiSeq 4000 sequencer (Biomarker Technologies, China). The obtained sequence reads were trimmed and mapped to the mouse reference genome (mm10) using HISAT2 (https://daehwankimlab.github.io/hisat2/), and gene expression and changes were analyzed using Cufflinks and Cuffdiff. Hierarchical cluster and scatter plot analyses of gene expression levels were performed using the R software (http://cran.r-project.org). GSEA was carried out as described (31), which was followed by network visualization in Cytoscape using the EnrichmentMap plugin (https://enrichmentmap.readthedocs.io/en/latest/).

Single iSG cells were prepared as described above. Single adult mouse DRG cells were prepared as described previously (49). In brief, DRGs were collected, transferred into a low-adhesion 6-cm pate with 2 ml of DMEM/F12 medium containing collagenase IV (1.25 mg/ml), and incubated at 37C in a 5% CO2 incubator for 50 min. Then, the medium was replaced with 2-ml DMEM/F12 medium containing 0.025% trypsin and incubated for 30 min. Following the addition of 2-ml DMEM/F12 medium containing 33% fetal bovine serum, all the medium was removed using a 10-ml pipette. After being washed three times with 2-ml HBSS, the DRGs were transferred into a 1.5-ml tube containing 1.2-ml DMEM/F12 and triturated by pipetting up and down several times using a 1-ml pipette to obtain single DRG cells. A Brn3b-GFP reporter mouse line was created using the CRISPR-Cas9 gene editing system to label adult RGCs by GFP, which were enriched by fluorescence-activated cell sorting. A more detailed description of this mouse line and RGC enrichment procedure will be published elsewhere.

The number and viability of prepared single cells were quantified using Countess II (Thermo Fisher Scientific, AMQAX1000). Next, single-cell libraries were generated with the Chromium Single Cell 3 V2 Chemistry Library Kit, Gel Bead & Multiplex Kit, and Chip Kit from 10x Genomics. In brief, cell suspension at concentration of 1.2 million/ml was loaded in a Single Cell 3 Chip along with the RT Single Cell 3 Gel Beads and the Partitioning oil, and Single Cell Gel Bead-In-Emulsions were generated in the Chromium Controller. Reverse transcription reaction was run to obtain complementary DNA (cDNA), which was amplified by PCR. To generate the libraries, Enzymatic Fragmentation, End Repair, and A-tailing Double Sided Size Selection were used to incorporate the barcodes and index read sequences. The libraries were qualified by bioanalyzer (Agilent Technologies) and quantified by a Qubit dsDNA High Sensitivity Assay kit (Invitrogen) and then sequenced on Illumina X Ten platform in 150 paired-end configuration.

Raw reads were processed using the 10x Genomics Cell Ranger pipeline (https://support.10xgenomics.com/single-cell-gene-expression/software/downloads/latest) with the mm10 as the reference. Cell Ranger can cluster the single cells, identify the marker genes of each cluster, and export a matrix with unique molecular identifier (UMI) values of each gene in a single cell. The R software package Seurat (https://satijalab.org/seurat, version 2.2) (33) was used for further analysis. Default parameters were used for most of the Seurat analyses. For the FeaturePlot function, max.cutoff was 0.5. The pseudotime trajectory analysis of iSG cells was performed using Monocle 2 (http://cole-trapnell-lab.github.io/monocle-release/) (35).

Statistical analysis was performed using the GraphPad Prism 7 and Microsoft Excel computer programs. The results are expressed as means SD for experiments conducted at least in triplicates. Unpaired two-tailed Students t test or one-way analysis of variance test were used to assess differences between two groups, and a value of P < 0.05 was considered statistically significant.

Acknowledgments: We thank E. Shiang for help with the artwork. Funding: This work was supported, in part, by the National Natural Science Foundation of China (81670862, 81721003, 31871497, 81870682, and 31700900), National Key R&D Program of China (2017YFA0104100, 2018YFA0108300, and 2017YFC1001300), National Basic Research Program (973 Program) of China (2015CB964600), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program, Science and Technology Planning Projects of Guangzhou City (201904020036 and 201904010358), China Postdoctoral Science Foundation (2019 M650223), and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology, Sun Yat-sen University. Author contributions: D.X., K.J., Y.S., and M.X. conceived and designed the research. D.X., Q.D., Y.G., X.H., M.Z., J.Z., P.R., Z.X., Y.L., and Y.H. performed the experiments and analyzed the data. D.X., K.J., and M.X. interpreted the data and wrote the manuscript. All authors contributed to critical reading of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. The RNA-seq and scRNA-seq data have been deposited in the NCBI Gene Expression Omnibus database under accession codes PRJNA595403 and PRJNA597624, respectively.

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Generation of self-organized sensory ganglion organoids and retinal ganglion cells from fibroblasts - Science Advances

BAR HARBOR Research by scientists at the MDI Biological Laboratoryis opening up new approaches to promoting tissue regeneration in organs damaged by disease or injury.

In recent years, research in regenerative biology has focused on stem cell therapies that reprogram the bodys own cells to replace damaged tissue, which is a complicated process because it involves turning genes in the cells nucleus on and off.

A recent paper in the journal Genetics by MDI Biological Laboratory scientist Elisabeth Marnik, Ph.D., a postdoctoral fellow in the laboratory of Dustin Updike, Ph.D., offers insight into an alternate pathway to regeneration: by recreating the properties of germ cells.

Germ cells, which are the precursors to the sperm and egg, are considered immortal because they are the only cells in the body with the potential to create an entirely new organism. The stem cell-like ability of germ cells to turn into any type of cell is called totipotency.

By getting a handle on what makes germ cells totipotent, we can promote regeneration by unlocking the stem cell-like properties of other cell types, said Updike. Our research shows that such cells can be reprogrammed by manipulating their cytoplasmic composition and chemistry, which would seem to be safer and easier than changing the DNA within a cells nucleus.

Using the tiny, soil-dwelling nematode worm, C. elegans, as a model, the Updike lab studies organelles called germ granules that reside in the cytoplasm (the contents of the cell outside of the nucleus) of germ cells. These organelles, which are conserved from nematodes to humans, are one of the keys to the remarkable attributes of germ cells, including the ability to differentiate into other types of cells.

In their recent paper entitled Germline Maintenance Through the Multifaceted Activities of GLH/Vasa in Caenorhabditis elegans P Granules, Updike and his team describe the intriguing and elusive role of Vasa proteins within germ granules in determining whether a cell is destined to become a germ cell with totipotent capabilities or a specific type of cell, like those that comprise muscle, nerves or skin.

Because of the role of Vasa proteins in preserving totipotency, an increased understanding of how such proteins work could lead to unprecedented approaches to de-differentiating cell types to promote regeneration; or alternatively, to new methods to turn off totipotency when it is no longer desirable, as in the case of cancer.

The increase in chronic and degenerative diseases caused by the aging of the population is driving demand for new therapies, said MDI Biological Laboratory President Hermann Haller, M.D. Dustins research on germ granules offers another route to repairing damaged tissues and organs in cases where therapeutic options are limited or non-existent, as well as an increased understanding of cancer.

Because of the complexity of the cellular chemistry, research on Vasa and other proteins found in germ granules is often overlooked, but that is rapidly changing especially among pharmaceutical companies as more scientists realize the impact and potential of such research, not only for regenerative medicine but also for an understanding of tumorigenesis, or cancer development, Updike said.

Recent research has found that some cancers are accompanied by the mis-expression of germ granule proteins, which are normally found only in germ cells. The mis-expression of these germ-granule proteins seems to promote the immortal properties of germ cells, and consequently tumorigenesis, with some germ-granule proteins now serving as prognosis markers for different types of cancer, Updike said.

Updike is a former postdoctoral researcher in the laboratory of Susan Strome, Ph.D., at University of California, Santa Cruz. Strome, who was inducted into the National Academy of Sciences last year, first discovered P granules more than 30 years ago. She credits Updike, who has published several seminal papers on the subject, with great imagination, determination and excellent technical skill in the pursuit of his goal of elucidating the function and biochemistry of these tiny organelles.

The lead author of the new study from the Updike laboratory, Elisabeth A. Marnik, Ph.D., will be launching her own laboratory at Husson University in Bangor, Maine, this fall. Other contributors include J. Heath Fuqua, Catherine S. Sharp, Jesse D. Rochester, Emily L. Xu and Sarah E. Holbrook. Their research was conducted at the Kathryn W. Davis Center for Regenerative Biology and Medicine at the MDI Biological Laboratory.

Updikes research is supported by a grant (R01 GM-113933) from the National Institute of General Medical Sciences (NIGMS), an institute of the National Institutes of Health (NIH). The equipment and cores used for part of the study were supported by NIGMS-NIH Centers of Biomedical Research Excellence and IDeA Networks of Biomedical Research Excellence grants P20 GM-104318 and P20 GM-203423, respectively.

We aim to improve human health and healthspan by uncovering basic mechanisms of tissue repair, aging and regeneration, translating our discoveries for the benefit of society and developing the next generation of scientific leaders. For more information, please visitmdibl.org.

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Research at MDI Biological Laboratory explores novel pathways of regeneration and tumorigenesis - Bangor Daily News

Most people are seeking the secret to anti-ageing, but did you ever wonder how the skin actually ages or how you could slow the process down?

Ageing is a natural process accompanied by a continuous alteration of the body. Your body produces visible changes in its structure, function and vulnerability to environmental stress and disease. Genetics, as well as the lifestyle we lead, play a big role in the ageing process.

Your skin is an organ, and its function is to regulate the excretion of metabolic waste products, regulate the bodies temperature as well as containing receptors for pain, tactile sensation, and pressure. Therefore, the health and appearance of your skin, like the health of your other organs correspond with your lifestyle and dietary habits, as well as with age-related factors such as the imbalance of hormones.

Ageing of the skin can be influenced by many factors including ultraviolet radiation, excess alcohol consumption, tobacco abuse, and environmental pollution.

What a lot of people dont realise is that as their body weight increases and their blood sugar levels rise, biochemical reactions interrupt the structural framework of their skin. With all these factors combined they lead to cumulative deterioration in the appearance of the skin as well as the function of the skin.

Within the skin ageing is associated with a loss of fibrous tissue, a slower rate of cellular renewal, and a reduced vascular and glandular network. The barrier function that maintains cellular hydration also becomes impaired. The subcutaneous tissue (known as the hypodermis or the third layer of the skin) flattens.

The rate at which these functions decline can be more than 50% by middle age depending upon ones genetic makeup, lifestyle and normal physiological functions within the skin. If we dont take action to support our skins intrinsic defence systems, the youthful qualities of our skin will deteriorate rapidly. Luckily for us, we can harness insights gathered through the latest scientific innovations and slow or potentially reverse the signs and symptoms of accelerated skin ageing.

Intrinsic skin ageing is primarily determined by genetic factors, hormonal imbalances and metabolic reactions like oxidative stress. Signs of intrinsic ageing include skin sagging, thinning and cracking, and the appearance of fine lines and wrinkles.

There are numerous external factors that affect the skin and cause signs and symptoms of premature ageing. Generally, most premature ageing is caused by over-exposure to the suns UV rays. However, there are other contributing factors, for example, atmospheric factors such as air pollution, visible light and infrared radiation. Lifestyle choices such as smoking, chronic stress and excessive alcohol consumption can lead to older-looking skin.

The most common signs of extrinsic ageing are thinning of the skin, laxity, fragility and the increased appearance of wrinkles.

As the skin is a visual organ, the beauty industrys main objective is to improve the appearance of skin with extensive topical treatments and products. However, often overlooked is the need to support the health and beauty of the skin from within.

Ideally one should centre their diet upon fruits, vegetables, whole grains, legumes, monounsaturated fats (like those found in olive oil), and a healthy ratio of omega-3 to omega-6 polyunsaturated fatty acids. Generally, consumption of shellfish, fish rich in omega 3 fatty acids, regular tea drinking, and greater consumption of fruits and vegetables have been known to be associated with improved skin health.

Gut health is crucial to healthy skin. The human skin hosts a variety of microorganisms, collectively known as the skin microbiota. Within the skin, there is a complex network of interactions between the microbes and cells. Friendly bacteria, such as Lactobacillus and Bifidobacteria are well researched for effectively treating infections, promoting healthy immunity, and reducing inflammation in the skin. Oral pre- and probiotics help to rebalance the skin microbiota and optimise the skin barrier function.

In addition, oral probiotics boost cellular antioxidant capacity and combat inflammation in general. Probiotics also help to neutralise toxic byproducts, defend the lining of the intestine, increase the bioavailability of some nutrients and reinforce the intestinal barrier against infectious microbes that may harm healthy skin.

Cosmeceuticals are topical products that exert both cosmetic and therapeutic benefits which have continued to evolve in order to ward off the signs of skin ageing. Some of the most popular topicals include exfoliating and depigmenting agents, antioxidants and regenerating products, such as peptides and stem cells.

Sunscreens (with dual protection against UVA and UVB in a photostable complex) are the most important topical as they protect us from the UV damage caused by the sun. Sun exposure is definitely one of the biggest contributing factors to premature ageing and is actually known as photo-ageing.

Another phenomenal topical is retinoids which have proven their safety and efficacy in reducing photo-damaged skin and are a popular treatment for anti-ageing. Retinoids help combat and reverse the visual effects of ageing, such as wrinkles, laxity, and discolouration. Retinoids accelerate cell turnover and can also improve blemishes and the appearance of pores.

The use of alpha-hydroxy acids (AHAs) has also been known to improve skin texture and reduce the signs of ageing by promoting the shedding of our superficial dead skin cells which in turn helps to restore hydration and a smoother texture. Whats nice about alpha-hydroxy acids is that they can pretty much treat any skin condition or concern because there are so many different types of acids. Theres literally something for everything. The most common ingredients used in product formulations and peels include citric acid, glycolic acid, lactic acid, malic acid, pyruvic acid as well as tartaric acid.

Antioxidants are being increasingly used in anti-ageing skincare. Topical antioxidants are effective in fending off damaging free radicals and reducing inflammation within the skin. A few popular ones used are ascorbic acid (vitamin C,) tocopherols (vitamin E,) alpha-lipoic acid and coenzyme Q10. Emerging natural antioxidants proving effective include EGCG (from green tea), resveratrol, Centella Asiatica (Gotu Kola,) proanthocyanidins (grapeseed,) curcumin, pomegranate, silymarin/silibinin (milk thistle), coffeeberry, melatonin, and marine-based ingredients.

Within the skin, the deterioration of collagen results in the formation of protein fragments, called peptides. These peptides are then recognised by collagen-producing cells, which respond by increasing collagen production in order to repair the damaged skin. However, as we age this positive feedback between skin breakdown and the initiation of new collagen formation becomes inefficient. Therefore by applying specialised peptides to your skin topically you can effectively trick collagen-producing cells into boosting collagen production. There are many other active ingredients used in topical products that are focused on anti-ageing among other things.

So basically all we need to do is protect the skin from the inside by consuming nutrient-packed foods as well as reducing our exposure to extrinsic factors that cause premature ageing along with using topical skincare products. Not as difficult as we may have thought, hey?

This content has been created as part of our freelancer relief programme. We are supporting journalists and freelance writers impacted by the economic slowdown caused by #lockdownlife.

If you are a freelancer looking to contribute to The South African,read more here.

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Ageing: An expos on what really causes us to show our age - The South African

Introducing the best in mens grooming for the year. The fourth and final segment in this series is a compilation of trusted head-to-toe treatment services every gentleman should indulge in to look and feel your best.Sometimes its better to leave things to an experts hands.

Treatment: CO2 Skin Renewal Facial Treatment, Porcelain

This treatment helps to deal with adult skin issues ranging from acne to ageing. To address the latter, a combination of a C02 mask and cryoprobes work to promote collagen production, boost blood circulation and tighten sagging skin. A hydrating enzyme mask then restores moisture and dissolves acne-causing grime and debris. Theres nothing to complain about when we left the compound with improved skin.Available at Porcelain for $298.50

Treatment: The Ultimate Shave Experience, Truefitt + Hill

We found out why people say its better to leave things to the experts. At this salon, the barber put us through an aromatic hot towel treatment to both soften our facial hair and help us relax. Swift and gentle strokes of the straight razor gave us a close shave, leaving our skin baby smooth and looking dapper fresh. We also appreciate the massage, which made us forget our worries and feel good to be alive.Available at Truefitt + Hill for $80

Treatment: Miracle Stem Cell Treatment, PHS Hairscience

This may not be as effective as a hair transplant, but it is a much less painful alternative to revive dormant hair follicles. The treatment uses the brands potent Miracle Stem Cell Solution, which contains a blend of growth factors, botanical stem cells and nutrients that nourish the scalp and encourage hair growth. DHT blockers neutralise the effects of androgen, the hormonal culprit behind hair loss.Available at PHS Hairscience for $297

Treatment: Rescue & Release Massage, Raffles Spa

Whether you pick the 60- or 90- minute option, this massage provides soothing relief from the tensions that city life inflicts. Swedish techniques were used to loosen tight knots, and this release of built-up tension left us feeling calmer and more in touch with our senses. The luxurious oils used in the treatment also left our skin feeling moisturised and nourished. Make time to use the baths to reap fuller relaxation benefits.Available at Raffles Hotel from $245

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AUGUSTMAN Grooming Awards 2020 Part IV: Best Head-To-Toe Treatment Services For Gentlemen - AUGUSTMAN

The global bioprinting market should reach $1.4 billion by 2024 from $306.2 million in 2019 at a compound annual growth rate (CAGR) of 35.4% for the period 2019 to 2024.

Report Scope:

This new BCC Research report on the topic Current Bioprinting Prospects and Future Innovations offers a detailed perspective on bioprinting technology, its current market and future prospects. The report provides a comprehensive analysis of the trending applications of bioprinting in the market in the global context, including market forecasts and sales through 2024. The report is focused on the analysis of the bioprinting market by various product types, regions and applications.

Get Access to sample pages @ https://www.trendsmarketresearch.com/report/sample/11647

The products that matter the most, i.e., instruments (bioprinters), reagents (bioinks), 3D cell culture products, and software and services, are discussed and analyzed. Each of these segments are sub-divided into different types (as detailed later). The emphasis is on the printing instruments, reagents, tissue products, skin substitutes, etc. The report also highlights the popular and emerging applications of bioprinting in the clinical and research domains. The end user markets, i.e., research and development, cosmetics, drug discovery, clinical and others, are analyzed in this report. Other end user markets include chemical, agrochemical, educational, hobbyist and veterinary applications. This study includes a survey of the bioprinting market in all geographic regions, including North America, Europe, and Emerging markets. The Emerging markets include regions like India, China, Korea, Taiwan, Africa, Australia, New Zealand, Canada, Latin America, among others.

The report elaborates on the critical issues and challenges facing the bioprinting industry as well as emerging trends in bioprinting technologies. It additionally features the new developments and new product launches in the global market.

The new BCC report provides relevant patent analysis and comprehensive profiles of market players in the industry. The industry structure chapter focuses on changing market trends, important manufacturers/suppliers, their market shares and product offerings. The chapter also covers mergers and acquisitions and any other collaborations or partnerships that happened during the evaluation period of this report that are expected to shape the industry.

Factors such as the strengths, weaknesses, threats and opportunities that are expected to play a role in the evolution of the bioprinting market are also evaluated. Any regulatory changes or new initiatives are highlighted explicitly.

Excluded from this report is medical 3D printing, which focuses on nonliving materials used in medical devices. Examples of medical devices that are not covered include treatment models, surgical tools and guides, prosthetics, dental restorations and crowns, and surgical implants.

Report Includes:

85 data tables and 27 additional tables Comprehensive analysis of the bioprinting technologies and their trending applications in the market at a global scale Analyses of the global market trends with data from 2017 to 2018, estimates for 2019, and projections of compound annual growth rates (CAGRs) through 2024 Segmentation of the global market by technologies and products, notably instruments (bioprinters), reagents (bioinks), 3D cell culture products, and software and services Focus on the popular and emerging applications of bioprinting in the clinical and research domains Regional dynamics of bioprinting technologies covering North America, Europe and Other emerging markets including India, China, Korea, Taiwan, Africa, Australia, New Zealand, Canada, Latin America etc. Discussion of new developments and new product launches in the global bioprinting market A relevant patent analysis Company profiles of market players in the industry, including 3Dynamic Systems Ltd., Aspect Biosystems, GeSiM, n3D Biosciences Inc., Organovo Holdings Inc., Prellis Biologics Inc. and regenHU Ltd.

Summary

Bioprinting is a form of additive manufacturing technology, that can be used to fabricate biomimicking 3D tissue constructs and organs. The reliability and accuracy offered by these 3D tissue structures and organ constructs have made them highly attractive for a number of applications. The use of stem cells in bioprinting has significant prospects in the area of personalized medicine, to develop customized tissues/organs for repair or for the fabrication of personalized 3D tissue models for drug toxicity testing.

There is a huge unmet demand for organs. Bioprinting of 3D organs has the potential to reduce the endless wait lists of organ donations and revolutionize the medical industry. Though a number of studies are going on catering to the development of fully, functional organs by bioprinting, a number of challenges remain. These pertain to the fabrication of complex tissues with multiple cell types, the issue of resolution, and the incorporation of vascularization, among other factors.

Despite these challenges, 3D bioprinting has undergone extensive progress and is used in many other applications. The 3D tissues being biofabricated can be used for tissue engineering and regenerative medicine. From the treatment of wounds (3D skin tissues), to craniomaxillofacial repair and orthopedic reconstructive surgeries (bone grafts), to the vascular grafts used to treat the growing number of heart disease patientsthese are just some of the potential clinical applications of bioprinting. In addition, in situ bioprinters that have the ability to treat the wounds/injuries by directly printing cells at a wound site are also gaining immense popularity.

One of the main drivers of the bioprinting market are the applications of 3D tissue constructs and biofabricated organ-on-chips for in vitro drug testing. The pharmaceutical industry is constrained by a high rate of drug failures at the clinical stage. Bioprinted 3D models reproduce natural tissues very closely and, therefore, are ideal materials for in vitro drug testing and other preclinical testing studies. The potential of 3D tissues to alleviate the burden on animal testing is another reason for their increased popularity. Poietis recently launched the biofabricated skin tissue, Poieskin, which can be used for cosmetic testing applications. Moreover, a multitude research organizations and universities aredeveloping 3D tissue models for disease modeling, drug research and cancer studies, among others.

The bioprinting market is propelled by innovations in bioprinting technologies and products encompassing bioprinters, bioinks, software, and 3D tissue products. The number of U.S. patents issued in 2018 (through November 4, 2018) in the field of bioprinting increased to 38, from a total of 27 in 2017. The highest number of patents were issued in the category of 3D cell culture products followed by the bioinks segment. Strategic collaborations and partnerships among research institutes and bioprinting companies along with interested partners from the pharmaceuticals and cosmetics sectors are supporting the growth of bioprinting market in a big way. Other factors driving the growth of the bioprinting market include increased government grants, the rising interest of private venture capitalists supporting several bioprinting start-ups, and the increasing healthcare burden.

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Bioprinting Market : Drivers, Restraints, Opportunities, and Threats 2018-2023 - Cole of Duty

Regenxbio (NASDAQ:RGNX) and Adverum (NASDAQ:ADVM) are both developing gene therapies for wet AMD. Phase I data is now available that shows both companies may have viable products. It is still very early, and small cohorts make it challenging to evaluate whether RGX-314 or ADVM-022 will be superior. Adverum's stock is priced as if it will deliver a product that is far superior to Regenxbio's. That outcome is far from certain. Investors should consider that Regenxbio's stock provides a wide margin of safety while offering tremendous upside if future data is positive.

Wet age-related macular degeneration, wet AMD, usually occurs in the elderly and accounts for 90 percent of the cases of legal blindness. In this condition, abnormal blood vessels in the retina begin to leak fluid. This results in scarring of the macula and vision loss. Symptoms include wavy, spotted or blurred vision. According to the Mayo Clinic, medications may help stop the growth of new blood vessels by blocking the effects of growth signals the body sends to generate new blood vessels. A protein called VEGF causes these abnormal blood vessels to grow. The current treatments are injections of anti-VEGF proteins into the eye which stop the growth of new blood vessels. These injections are required every four to eight weeks, and patients tend not to adhere to this difficult schedule and thus suffer vision loss.

These drugs are considered the first line treatment for all stages of wet macular degeneration. The most commonly prescribed injections are Avastin (Genentech) (OTCQX:RHHBY), Lucentis (Genentech) and Eylea (Regeneron (REGN)). A longer acting version that can last 12 weeks, brolucizumab, was approved in 2019, but it may cause occlusive retinal vasculitis, a rare but serious complication that can cause vision loss, which may make ophthalmologists hesitant to use it.

Wet AMD is a disease where the biology is well understood. More specifically, it is well understood that anti-VEGF proteins such as Avastin, Lucentis and Eylea are effective at preventing these "bad blood vessels" from growing. There is extensive proof that if you maintain anti-VEGF activity in the eye, which gene therapy seeks to achieve, you can prevent a loss of vision in wet AMD. Both Regenxbio and Adverum have gene therapy candidates in clinical trials which seek to provide a consistent level of anti-VEGF activity.

Wet AMD is not thought to be caused by a genetic defect but a one time gene therapy injection can provide a treatment option. This involves inserting a transgene, which would produce the anti-VEGF proteins, into a viral vector which can be delivered to the eye. The result is that the eye turns into a factory that produces the needed protein. Since the cells in the eye make their own protein, patients have no need or a reduced need for repeated injections. The goal is for these treatments to be durable enough to last a lifetime and reduce the enormous treatment burden of requiring frequent injections. A report in Science Daily, citing the American Academy of Ophthalmology as their source, noted that researchers believe that, "It's not just about convenience; a more consistent treatment may also help people keep more of their vision." Gene therapy seeks to achieve this by delivering a steady daily dose of anti-VEGF.

Globally, $10 billion is expected to be spent on treatments for this disorder by 2024. There are more than 1.2 million patients with wet AMD in the US and a total of 3 million globally. There is a large market opportunity for both players, but it is important to note that gene therapy is unlikely to take over the entire market as there are long acting anti-VEGF treatments in clinical trials that may also reduce the treatment burden. In addition, patients may have the option of a port delivery systems that can be refilled. Given these potential options, gene therapy may take a large market share, but it is unlikely to be one hundred percent of the market. According to Dr. Peter Campochiaro, MD, Director of the Retinal Cell and Molecular Laboratory at Johns Hopkins, who is a RGX-314 investigator, the main competitor to gene therapy will be ports.

Regenxbio has their own internal pipeline, including RGX-314 in the treatment of wet AMD. In an article published in Retina Today, Drs. Allen Ho and Robert Avery describe the nature of the treatment.

"RGX-314 is a non-replicating, recombinant AAV serotype 8 (AAV8) vector encoding for a soluble anti-VEGF Fab protein, which binds to retinal pigment epithelial cells to produce a therapeutic anti-VEGF protein. The gene encodes for an anti-VEGF fragment of an antibody that is similar to ranibuzumab."

Simply put, RGX-314 is a harmless virus which will direct the eye to produce an anti-VEGF medication, which is similar to an FDA approved drug.

Regenxbio has been using subretinal injections which require a surgical procedure in their Phase I studies to date. Going forward, they will also concurrently be testing a micro injector that targets the suprachoroidal space. This approach is being tested based on research done at Johns Hopkins that indicates that this approach, which could be done in the office, could be equally effective. From the physician and patient's standpoint, an in-office delivery would be superior to a surgical procedure.

Regenxbio is licensing the micro injector for suprachoroidal injections from Clearside Biomedical (CLSD) and will begin testing it in a Phase II trial of RGX-314. Regenxbio will be advancing both the subretinal and suprachoroidal approach into Phase II during the second half of 2020. In an article published in Molecular Therapy, researchers noted differences in the cells that have shown transduction depending on the route of administration.

"We found that suprachoroidal AAV8 delivery produced diffuse, peripheral transduction of mostly RPE, while subretinal injection using transscleral microneedles led to a robust, but localized area of gene transfer to multiple retinal cell types."

An article written by Peter Campochiaro, MD of Johns Hopkins noted that,

"Total transgene expression after a single suprachoroidal injection of AAV8 vector is comparable to that seen after subretinal injection of the same vector dose, and can be increased by multiple suprachoroidal vector injections."

This research supports that the more convenient suprachoroidal administration can be effective at producing the needed protein. Clearside Biomedical has a product through Phase 3 trials that validates the efficacy of suprachoroidal administration.

Adverum has a competing gene therapy product in the clinic. According to the company,

"ADVM-022 uses a proprietary capsid (AAV.7m8) to deliver a proprietary expression cassette which expresses aflibercept. ADVM-022 is administered as a single intravitreal injection and is designed to minimize the treatment burden of repeated anti-VEGF injections."

This gene therapy can be a straightforward one time injection which can be performed in the office. According to Dr. David Brown of Baylor College of Medicine, some studies show aflibercept is probably the best drying agent. However, intravitreal injections of AAVs can have negative side effects. Research published in the journal Molecular Therapy noted that

"Intravitreal AAV causes more intraocular inflammation and elicits a more potent humoral immune response than does subretinal administration."

This inflammation has been managed with oral and topical steroids which have not been required thus far for patients receiving RGX-314.

Regenxbio and Adverum are using different AAV's, different methods of administration and different transgenes. The transgenes used in RGX-314 and ADVM-022 differ in which anti VEGF protein they deliver. In a clinical study of 965 eyes that compared aflibercept (ADVM-022's transgene) to ranibizumab (RGX-314's transgene), they were equally effective in wet AMD. Therefore, it is likely both transgenes are equally effective.

Regenxbio has released two year data on cohorts 1-3 showing safety and efficacy as well as the durability of the treatment. They have dosed all 5 cohorts but long term data is not yet available for cohorts 4 and 5. Adverum has data out to 64 weeks for their first two cohorts and has early data on cohort 3. The last group, cohort 4, was recently dosed. These Phase I/IIa studies are two years in length so Regenxbio has the lead by at least 10 months. Should both treatments show efficacy and safety, RGX-314 is likely to be first to market.

Physicians often use a new product which is first in its class and become comfortable with the risks, benefits, side effects and administration. Unless there is a perception that other products of the same class offer a benefit, they often continue to use the first in class product. If RGX-314 proves to have a favorable profile, the first to market advantage will be significant. It should be acknowledged that gene therapy may be slightly different as these are one time administration products and physicians may wait if they believe a product (such as ADVM-022) that is coming soon will be superior.

Adverum reported that 14/17 patients have not needed rescue injections reflecting an impressive 82 percent rescue free injection rate for patients in cohorts 1-3.

For Regenxbio's cohorts 1 and 2, the dosage used appears to be suboptimal, so it is logical they would not choose these doses going forward. The doses in Cohort 3-5 appear to be more effective. Cohort 3 had 4/5 patients rescue free if you remove data from a patient who had a procedure that failed to deliver a full dosage of the drug. Another patient who initially required rescue injections but later became rescue free can be considered a responder in this cohort. Cohort 4 had 5/12 patients rescue free and cohort 5 currently has 8/11 patients rescue free. The overall rescue free rate for Regenxbio's cohorts 3-5 is 17/28 or only 61 percent.

Adverum's data is clearly better in terms of the number of patients who did not require rescue injections, 82% vs 61%. Adverum had less stringent criteria for when a rescue injection can be given - the loss of 10 letters due to fluid rather than 5 letters which Regenxbio used. Adverum previously guided that no patient would have required rescue injections had the criteria been 5 letters. If larger studies replicate these rescue free rates, it is questionable whether RGX-314 will be competitive.

Some of this differential in the percentage of patients requiring rescue injections could be due to the variability in response to anti-VEGF therapy between individual patients. Dr. Charles Wykoff of Retina Consultants of Houston commented on this variability. Dr. Wykoff noted that

"it's rare to find an individual who has no response to anti-VEGF therapy." However, "a significant number of wet AMD patients are recalcitrant," "We inject them repeatedly, but they continue to show fluid. However, that's not the same as being a 'non responder.'"

In Regenxbio's cohort, 4 only 5/12 patients were rescue free. Some of these patients may be what Dr. Wykoff calls recalcitrant in that even though they have high anti-VEGF protein levels, they still have fluid. The high protein levels in this cohort would support that these particular patients may be very difficult to "dry out." Given that the protein levels were higher in cohort 4 than 3, and cohort 3 patients had an 80 percent rescue free rate, this seems to support that patients in cohort 4 had a very high anti-VEGF demand.

Figure 1: Regenxbio Corporate Presentation

For some patients, gene therapy may be a one time solution. For others, gene therapy may be an adjunctive therapy that reduces the number of injections. The fact that some patients will still need injections will likely be a subject insurers wish to discuss when considering pricing.

Adverum has data for 3 cohorts which included a total of 21 patients at two doses. Of those twelve patients for whom there is at least one year data, only 3 of the 12 had any improvement in BCVA. Looking at the individual data for BCVA gives us a clearer picture. BCVA through December 1, 2019, for Cohort 1 was: +7, -6, -7, +5, -2, -3. BCVA for Cohort 2 was -4, -1, -19, -14, -7, +16. For patients who required very few rescue injections, this is disappointing data for visual acuity. Cohort one and two lost 2.7 and 2.8 letters, respectively, at the last update provided. Short-term results (up to 20 weeks) for cohort 3 showed an increase of 6.8 letters. The lack of individual patient data makes it hard to assess whether the general trend was an improvement in visual acuity. If you average this across all cohorts, there is approximately a 1.3 letter improvement. Cohort 2 and 3 used the same dosage but Cohort 3 used topical steroid drops rather than oral steroids so perhaps this accounts for the improvement in BCVA. Although cohort 3's data is greatly improved in comparison to cohorts 1 and 2, it remains an unanswered question whether Phase II patients will show a similar improvement in vision.

Regenxbio took the approach of 5 cohorts with increasing dosages. For cohort 3, in considering BCVA figures, it is reasonable to remove results from a patient who had a procedure error and did not receive a full dosage of the study drug. That leaves 5 patients with BCVA changes of (+32, +17, +6, +7 and +25). Cohort 4 for which Regenxbio has not released individual patient data had a BCVA improvement of +2 for the twelve patients. The lack of individual patient data makes it hard to assess whether the general trend was an improvement in visual acuity. Early data from Cohort 5 showed that responders saw a +5 letter improvement in BCVA. Combining the Regenxbio data from Cohorts 3-5, with the limitation that we don't have BCVA for those who required rescue injections in cohort 5, gives an approximately +6 letter improvement.

The general trend is that BCVA is superior for RGX-314 when compared to ADVM-022. Visual acuity data for RGX-314 more closely parallels what is seen with the standard of care treatments. Studies of the standard of care drugs such as ranibizumab (RGX-314 transgene) showed a +7.2 mean letter change in BCVA after a year. The same study found that aflibercept (ADVM-022 transgene) produced a +4.9 mean change in BCVA letter score. For context, Adverum's data on BCVA (+1.34 letters) is worse than the data from standard of care studies. Most studies show a maximum of 8-11 letter improvement for wet AMD patients treated with anti-VEGF medications. In this context, Adverum's 1.3 letter improvement is concerning.

It is also possible that some of Adverum's patients fall into the category some retinal specialists call "treatment disappointments," where the fluid is removed but patients fail to have any improvement in vision. Given the small number of patients, it is difficult to extrapolate whether this trend in visual acuity would persist in studies with a large number of patients. Another factor to be considered is that "intravitreal AAVs causes more intraocular inflammation and elicits a more potent humoral immune response than does subretinal administration." It is unknown if this inflammation has any impact on vision but cohort 3, where inflammation was managed with steroid drops, did show an improvement in visual acuity.

Another explanation for the difference in outcome in visual acuity between RGX-314 and ADVM-022 may be that "baseline BCVA is one of the strongest predictors of visual acuity gains." Specifically, patients with "the highest baseline BCVA had lowest BCVA gains." Adverum's patients across all three cohorts had a baseline mean BCVA of approximately 65.5 vs 55.7 for Regenxbio. This could partially explain a difference in gains - Adverum's patients had less to gain. However, 5 of the patients in cohorts 1 and 2 had significant vision loss (-6, -7, -19, -14, -7), and this is highly concerning. There was no patient specific data released for cohort 3, and this is also a concern as one patient with a very impressive gain can conceal the pattern of most patients losing vision. It is encouraging to see positive data for cohort 3, but it is not prudent to ignore the data from the other two cohorts.

Most studies in wet AMD for the standard of care define success as a stabilization of vision loss. However, an article published in Review of Ophthalmology written by ophthalmologists at Barnes Retina Institute of Washington University commented on the evolving goals of treatment. They wrote that "as standards for treatment success are raised, more attention should be focused on visual acuity gains as the primary endpoint." One of the outcomes sought by developers of gene therapy is to provide a continual dose of anti-VEGF therapy that results in improved vision rather than the gradual decline in vision seen in real world studies of standard of care treatments. In this context, ADVM-022's results in visual acuity fall short.

Adverum shares are trading around $20, and the company has a market cap of approximately 1.6 billion reflecting a rich valuation even considering that the company has cash on hand to fund operations through 2022. ADVM-022 is a "one hit wonder", and the company has no other products in clinical trials should ADVM-022 fail or fail to deliver an extraordinary safety and efficacy profile. The current share price of Adverum assumes a very low risk of failure for a product, which is still in Phase I/IIa trials. This valuation also reflects expectations that ADVM-022 will be a superior gene therapy treatment and capture a large percentage of the gene therapy market.

RGNX is trading around $41 and has a market cap of approximately $1.6 billion, the same market cap that Adverum has. Just as Adverum, Regenxbio has cash on hand sufficient to fund their internal pipeline costs through 2022, so dilution is not a near-term risk. Regenxbio is a much more diverse company than Adverum, and the value of their other assets is substantial. Their internal pipeline has 4 products in clinical trials, although RGX-314 has by far the greatest commercial opportunity.

In addition to an internal pipeline, Regenxbio licenses intellectual property to partners who are engaged in 26 different gene therapy programs. This revenue stream is significant and should grow with time. Novartis (NYSE:NVS) sells a gene therapy, Zolgensma, for SMA which uses one of Regenxbio's AAVs. Regenxbio reported that Novartis, which started selling Zolgensma in the second quarter of 2019, has reached $530 million in sales as of the first quarter of 2020. Regenxbio receives approximately ten percent of sales as a royalty payment. This product is likely to exceed a billion dollars in sales by 2021 and perhaps have peak sales as high as $2.5 billion annually providing a secure revenue stream for Regenxbio to pursue their internal pipeline.

Regenxbio is also investing in manufacturing which "will allow for production of NAV Technology-based vectors at scales up to 2,000 liters using REGENXBIO's platform suspension cell culture process." Manufacturing capability is a very undervalued asset considering that "Thermo Fisher paid $1.7 billion last year to buy viral vector contract manufacturer Brammer Bio" and is further investing $180 million to build a new gene therapy plant. Catalent (NYSE:CTLT) last year paid $1.2 billion for Paragon Bioservices to bolster its manufacturing capacity for gene therapies further validating the value of gene therapy manufacturing infrastructure. The licensing revenue, three other products in the pipeline and the intrinsic value of the manufacturing infrastructure provide a margin of safety if RGX-314 disappoints in clinical trials.

There are concerning aspects of both Regenxbio's data (the need for rescue injections) and Adverum's data (the poor outcomes in visual acuity). Should ADVM-022 not prove to give vision improvements, the benefit of reduced rescue injections will not be as meaningful. Wet AMD is treated to prevent blindness and to improve vision. Therefore, it is logical that vision improvement is a goal and perhaps the most important metric of all. Along a similar line of reasoning, if only 60 percent of the patients are rescue injection free, it brings into question whether physicians would administer RGX-314 if ADVM-022 provided a much greater chance of requiring no rescue injections.

Assessing early data is extremely difficult. Trends that appear in Phase I can completely disappear in Phases II and III which involve larger cohorts with a more diverse set of patient characteristics. There is a wide range of responses from individual patients to the same treatment which makes it essential to see responses in large groups. Some side effects or efficacy patterns are not revealed until after FDA approval when a medication is used in even larger patient populations. These truths highlight the difficulty of drawing conclusions based on sample sizes as small as 6 patients in a cohort. Thirty percent of drugs fail in Phase 2 further reinforcing that early data that looked very promising can be misleading when larger cohorts are studied.

In this case, it is so early that NO data is yet available in the suprachoroidal administration of RGX-314. The lack of data in this administration makes it particularly difficult to compare RGX-314 to ADVM-022. Given this would be the preferred route of administration, this data is what is most important to assess in comparison to ADVM-022. In addition, both companies are still assessing varying dosages so it is far from clear at this moment what the final product that physicians would choose from would look like.

Larger data sets will be forthcoming in the next twelve to eighteen months which will provide greater clarity about whether RGX-314, ADVM-022 or both will be viable commercial products. Investors should keep a close eye on larger data sets and critically evaluate how these products compare. Investors considering diving into the wet AMD gene therapy market should also consider the wide margin of safety that Regenxbio's more diverse pipeline, secure licensing revenue and manufacturing assets provide.

Disclosure: I am/we are long ADVM, RGNX. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.

Additional disclosure: This article is for information purposes only and does not constitute a recommendation to buy or sell any security.

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The Wet AMD Gene Therapy Race - Adverum Biotechnologies Vs. Regenxbio - Seeking Alpha

The Gene Therapy Products market analysis report contains a skilful and deep analysis of the present situation and challenges. This business report focuses on the key drivers, restraints, market opportunities, threats and risks for market major players. It also makes available analysis of market size, shares, growth, segmentation, revenue projection (USD Mn), and regional study till 2026. The market research document offers a wide-ranging overview of the global Gene Therapy Products market and contains thoughtful insights, facts, historical information, and statistically supported & industry-verified market data. This report comprises of forecasts that uses a suitable set of predictions and distinct research methodologies. Global Gene Therapy Products market document helps identify the latest growths, market shares, and policies employed by the major market players.

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Global gene therapy products market is set to witness a substantial CAGR in the forecast period of 2019- 2026. The report contains data of the base year 2018 and historic year 2017. Rising cancer cases and unused potential for emerging markets are the major factors for the growth of this market.

Few of the major competitors currently working in the globalgene therapy products marketareAdaptimmune., Anchiano Therapeutics, bluebird bio, Inc., CELGENE CORPORATION, GlaxoSmithKline plc., Merck KGaA, Novartis AG, Achieve Life Sciences, Inc., Spark Therapeutics, Inc., Abeona Therapeutics, Inc, Adverum, agtc, Arbutus Biopharma, Audentes Therapeutics, AveXis, Inc., CRISPR Therapeutics, Intellia Therapeutics, Inc and Gilead Sciences,Inc. among others.

Market Definition:Global Gene Therapy Products Market

Gene therapy or human gene therapy is a process which is used to modify gene for the treatment of any disease. Plasmid DNA, bacterial vector, human gene editing technology and viral vectors are some of the most common type of gene therapy products. The main aim of the gene therapy is to replace the dysfunctional genes. Somatic and germline are some of the most common type of the gene therapy.

Complete report on Global Gene Therapy Product Market Research Report 2019-2026 spread across 350 Pages, profiling Top companies and supports with tables and figures

Segmentation: Global Gene Therapy Products Market

Gene Therapy Products Market : By Product

Gene Therapy Products Market : By Application

Gene Therapy Products Market : ByGeography

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Key Developments in the Gene Therapy Products Market:

Gene Therapy Products Market Drivers

Gene Therapy Products Market Restraints

Competitive Analysis: Gene Therapy Products Market

Global gene therapy products market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of gene therapy products market for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Key questions answered in the report :-

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Gene Therapy Products Market 2020 Upcoming Opportunities | Key Players Novartis AG, Achieve Life Sciences, Inc., Spark Therapeutics, Inc., Abeona...

- Smart Medical Services powered by IoT and Sensors Key to Vast Avenues in Emerging Markets, particularly Asia Pacific; Governments Become Payers, Providers, and Policy Makers, thereby accelerating Growth of Smart Healthcare Products Market

- Application in Patient Treatments and Diagnostics Key to Growth; Digitization in Healthcare Industry Forms Key Underpinning to Market Expansion

ALBANY, New York, May 28, 2020 /PRNewswire/ --The smart healthcare products market has evolved on the back of the proposition of making medical and patient care more efficient, affordable, and accessible. Rapid pace of digitization in the healthcare industry on account of integration of an array of technologies such as sensors, IoT framework, smart data analytics with healthcare products contributes to broadening avenues in the market. Smart healthcare gadgets play crucial role in accessing patient data remotely and help in monitoring of chronic conditions.

The latest valuation of the smart healthcare products market was estimated to be US$ 37.5 Bn in 2018. Expanding at CAGR of 8.8% from 2019 to 2027, the global smart healthcare products market is anticipated to reach worth of US$ 80.3 bn by this period-end.

Increasing share of healthcare spending in the GDP of several countries will focus on adoption of smart healthcare products for patient care, note the analysts at Transparency Market Research. They further concede that addressing cost and privacy concerns should be crucial in making healthcare IT successful for disease diagnosis and treatment.

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Key Findings of Smart Healthcare Products Market

Explore 90 pages of top-notch research, incisive insights, and detailed country-level projections. Gain business intelligence on Smart Healthcare Products Market (By Product Type - Smart Syringes, Smart Pills, Smart RFID Cabinets and Electronic Health Record; By Application - Health Data Storage and Exchange, Monitoring and Treatment, and Inventory Management - Global Industry Analysis, Size, Share, Growth, Trends and Forecast 2019 2027 at https://www.transparencymarketresearch.com/report-toc/9437

Smart Healthcare Products Market: Key Driving Factors and Promising Avenues

A favorable macroeconomic framework in numerous countries is key to the rapid expansion of global smart healthcare products market. Few of the trends are worth noticing.

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Key Challenges for Players in Smart Healthcare Products Market

The smart healthcare products market has made some incredible strides in developing and developed world, unarguably. But a few concerns offset the gains of their uptake in the healthcare industry as following:

Nevertheless, the factors highlighting the silver lining are more than one:

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The global smart healthcare products market has been segmented as follows:

Explore Transparency Market Research's award-winning coverage of the global Healthcare industry:

Swab and Viral Transport Medium Market The global swab and viral transport medium market is primarily driven by increase in demand for swabs & viral transport medium owing to COVID-19 pandemic, rise in use of viral transport medium in microbiology & diagnostic laboratories, and high investment in diagnostic equipment, kits, and accessories. Increase in the geriatric population, rise in adoption of diagnostic tests, and growth of the diagnostics industry are the other factors projected to drive the global market during the forecast period.

Cell and Gene Therapy Market Technological advancements in cell and gene therapy is one of the key factors projected to fuel the global cell and gene therapy market during the forecast period. Emerging technologies in cell and gene therapies, such as proprietary cell lines, gene vectors, cell expansion and separation systems, and single-use bioprocessing reactors, have become primary means by which single products have been transformed into a robust product portfolio. For example, Immunicum has offered three technological platforms i.e. gene editing, CAR-T cell expansion, and T-cell primers. These technologies allow the company to advance its series of immuno-oncology drug candidates. Immunicum has two technologies i.e. IMM-2 platform and IMM-3 platform undergoing preclinical studies for use in the treatment of different types of cancer. Immunicum is looking forward to developing an allogeneic dendritic cell in-vivo vaccine for use in the treatment of solid tumors.

Antivirals Market- Some of the primary trends in the global market for antivirals are the development of new mechanisms and research on second-generation molecules, combination therapies, and topical administration routes. Investors proactively pursue research and development of drug candidates for viral diseases that require long-term treatment. They also prefer initiatives that have a predominant patient-base in developed regions of the world and are readily accepted by physicians and drug formularies. Antivirals ideally fit the profile and hence are gaining strong investments. Moreover, the need to improve the quality of life of the patients on the available antiviral regimens is encouraging efforts for the development of second-generation molecules, such as IFN-.

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Smart Pills Expand Horizon of Smart Healthcare Products; Market to Clock CAGR of 8.8% From 2019 to 2027, Finds Transparency Market Research - PR...

The report on the Hemophilia Gene Therapy market provides a birds eye view of the current proceeding within the Hemophilia Gene Therapy market. Further, the report also takes into account the impact of the novel COVID-19 pandemic on the Hemophilia Gene Therapy market and offers a clear assessment of the projected market fluctuations during the forecast period. The different factors that are likely to impact the overall dynamics of the Hemophilia Gene Therapy market over the forecast period (2019-2029) including the current trends, growth opportunities, restraining factors, and more are discussed in detail in the market study.

The Hemophilia Gene Therapy market study is a well-researched report encompassing a detailed analysis of this industry with respect to certain parameters such as the product capacity as well as the overall market remuneration. The report enumerates details about production and consumption patterns in the business as well, in addition to the current scenario of the Hemophilia Gene Therapy market and the trends that will prevail in this industry.

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What pointers are covered in the Hemophilia Gene Therapy market research study?

The Hemophilia Gene Therapy market report Elucidated with regards to the regional landscape of the industry:

The geographical reach of the Hemophilia Gene Therapy market has been meticulously segmented into United States, China, Europe, Japan, Southeast Asia & India, according to the report.

The research enumerates the consumption market share of every region in minute detail, in conjunction with the production market share and revenue.

Also, the report is inclusive of the growth rate that each region is projected to register over the estimated period.

The Hemophilia Gene Therapy market report Elucidated with regards to the competitive landscape of the industry:

The competitive expanse of this business has been flawlessly categorized into companies such as

Competition AnalysisIn the competitive analysis section of the report, leading as well as prominent players of the global Hemophilia Gene Therapy market are broadly studied on the basis of key factors. The report offers comprehensive analysis and accurate statistics on revenue by the player for the period 2015-2020. It also offers detailed analysis supported by reliable statistics on price and revenue (global level) by player for the period 2015-2020.On the whole, the report proves to be an effective tool that players can use to gain a competitive edge over their competitors and ensure lasting success in the global Hemophilia Gene Therapy market. All of the findings, data, and information provided in the report are validated and revalidated with the help of trustworthy sources. The analysts who have authored the report took a unique and industry-best research and analysis approach for an in-depth study of the global Hemophilia Gene Therapy market.The following players are covered in this report:Spark TherapeuticsUltragenyxShire PLCSangamo TherapeuticsBioverativBioMarinuniQureFreeline TherapeuticsHemophilia Gene Therapy Breakdown Data by TypeHemophilia AHemophilia BHemophilia Gene Therapy Breakdown Data by ApplicationHemophilia A Gene TherapyHemophilia B Gene Therapy

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Exclusive details pertaining to the contribution that every firm has made to the industry have been outlined in the study. Not to mention, a brief gist of the company description has been provided as well.

Substantial information subject to the production patterns of each firm and the area that is catered to, has been elucidated.

The valuation that each company holds, in tandem with the description as well as substantial specifications of the manufactured products have been enumerated in the study as well.

The Hemophilia Gene Therapy market research study conscientiously mentions a separate section that enumerates details with regards to major parameters like the price fads of key raw material and industrial chain analysis, not to mention, details about the suppliers of the raw material. That said, it is pivotal to mention that the Hemophilia Gene Therapy market report also expounds an analysis of the industry distribution chain, further advancing on aspects such as important distributors and the customer pool.

The Hemophilia Gene Therapy market report enumerates information about the industry in terms of market share, market size, revenue forecasts, and regional outlook. The report further illustrates competitive insights of key players in the business vertical followed by an overview of their diverse portfolios and growth strategies.

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COVID-19 impact: Insight on the Growth of Hemophilia Gene Therapy Market Growth with Challenges, Standardization, Competitive Market Share and Top...

Another day, another win for Enhertu.

The antibody-drug conjugate AstraZeneca promised up-to $7 billion to partner on has had a quite a few months, beginning with splashy results in a Phase II breast cancer trial, a rapid approval and, earlier this month, breakthrough designations in both non-small cell lung cancer and gastric cancer.

Now, at ASCO, the British pharma and their Japanese partner, Daiichi Sankyo, have shown off the data that led to the gastric cancer designation, which theyll take back to the FDA. In a pivotal, 187-person Phase II trial, Enhertu shrunk tumors in 42.9% of third-line patients with HER2-positive stomach cancer, compared with 12.5% in a control arm where doctors prescribed their choice of therapy. Progression-free survival was 5.4 months for Enhertu compared to 3.5 months for the control.

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Headed to PhII: Allogene CEO David Chang completes a positive early snapshot of their off-the-shelf CAR-T pioneer - Endpoints News

Its reasonableto assume immunotherapies such as PD-1 inhibitors, which unleashthe bodys own immune system to target and destroy cancer, work best in hot tumors that are flooded with immune cells in their microenvironment. But a new study by scientists at the Dana-Farber Cancer Institute found that is not the case in kidney cancer.

The researchers discovered that in advanced clear cell renal cell carcinoma (ccRCC)the most common form of kidney cancertumors that were infiltrated with large numbers of CD8 T cells were less likely to respond to Bristol Myers Squibbs PD-1 inhibitor Opdivo than cold tumors were.

The findings, presented at the American Society of Clinical Oncology virtual event and published in Nature Medicine, provide critical insights that may help predict which patients are more likely to benefit from immuno-oncology agents, the researchers argued.

The Dana-Faber scientists examined 592 tumors collected from three Opdivo kidney cancer clinical trials in an attempt to draw a correlation between patient outcomes and immune and genomic biomarkers. They discovered that kidney cancer deviates from several well-known tenets of cancer treatment. Normally, tumors containing a large number of neoantigensproteins formed as a result of tumor mutations and therefore new to the immune systemare often more susceptible to immunotherapy. But that didnt affect ccRCC responsiveness to Opdivo, the team found.

Perhaps most surprisingly, hot tumors with high levels of CD8 T cells didnt respond well to Opdivo, either. But why?

The researchers found that these hot tumors were depleted of mutated PBRM1 genes, which are often associated with improved survival from PD-1 blockade. Instead, they had more of an unfavorable genetic featurethe loss of a chromosomal segment called 9p21.3. When found within hot tumors, deletion of 9p21.3 was associated with worse clinical benefit and survival after PD-1 treatment.

We believe that these two factors may explain why CD8 T cell infiltration of the tumors did not make them responsive to checkpoint blocker therapy, while other types of cancer that exhibited CD8 T cell infiltration but did not have those chromosomal changes did respond, explained co-authorSachet Shukla, Ph.D., chief of the computational group at the Dana-Farber Translational Immunogenomics Laboratory,in a statement.

RELATED:Could the anti-cancer gene p53 be a target in treating kidney cancer?

The Dana-Farber study offers clues to mechanisms that contribute to response and resistance to PD-1 drugs in ccRCC and possibly other types of tumors as well, the researchers suggested. It can help identify patients most suitable for these immuno-oncology drugs and provide fundamental information to aid in development of rational combination therapies to overcome resistance in the future, said study co-author Toni Choueiri, M.D., director of the Lank Center for Genitourinary Oncology at Dana-Farber.

The presence of high numbers oftumor-infiltrating immune cells isoften linked to better immunotherapy treatment outcomes. Thats why scientists are constantly looking for ways to turn coldtumors hot. In October, a Yale University team described a method for using gene-editing system CRISPR to make tough-to-spot tumors more visible to the immune system.

Another approach aimed at improving immuno-oncology in kidney cancer involves combining immune-boosting treatments. A combo of BMS' Yervoy with Opdivo was approved for first-line treatment of kidney cancer in 2018. In February of this year, the company unveiled new data showing 56% of patients taking the combo in a trial were still alive at 42 months, versus 47% of patients taking Pfizer's Sutent alone.

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Why 'hot' kidney tumors don't respond to immunotherapy with PD-1 blockers - FierceBiotech

Facts and Factors recently published a market study onCell and Gene Therapy Consumables. This study examines detailed assessment of key market dynamics, including the drivers, trends, opportunities & restraints, and detailed information about the Cell and Gene Therapy Consumables market structure. The market study suggests that the global market size of Cell and Gene Therapy Consumablesnts is projected to reach a CAGR of xx% over the stipulated timeframe 2020-2026.

The Cell and Gene Therapy Consumables market report analyses and notifies the industry statistics at the global as well as regional and country levels to acquire a thorough perspective of the entire Cell and Gene Therapy Consumables market. The historical and past insights are provided for FY 2016 to FY 2019 whereas projected trends are delivered for FY 2020 to FY 2026. The quantitative and numerical data is represented in terms of value from FY 2016 2026.

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Impact of COVID-19 Pandemic on Global Economy

The study also offers scrutiny of the changing government policies amid COVID-19 disruptions. The COVID-19 outbreak has affected economies and industries in various countries due to lockdowns, travel bans, and business shutdowns. Policymakers in developing and developed nations are framing and changing new regulations to meet the continuing macrocosmic shocks by COVID-19 pandemic. The authors of the report have taken into account the impact analysis of the pandemic, and have elaborated on the trends that will be crucial to the upcoming competitive landscape.

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This report presents a comprehensive overview, market shares, and growth opportunities of Cell and Gene Therapy Consumables market by product type, application, key manufacturers and key regions and countries. In addition, this report discusses the key drivers influencing market growth, opportunities, the challenges, and the risks faced by key manufacturers and the market as a whole. It also analyses key emerging trends and their impact on present and future development.

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Cell and Gene Therapy Consumables Market Size Outlook 2020 Report with COVID-19 Analysis Forecast till 2026 - Bandera County Courier

Global Gene Therapy Market Report is a professional and in-depth research report on the worlds major regional market. The Gene Therapy industry2020 by Industry Demand, Business Strategy & Emerging Trends by Leading Players. The Global pandemic of COVID19/CORONA Virus calls for redefining of business strategies. This Gene Therapy Market report includes the impact analysis necessary for the same.

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Top Players Listed in the Gene Therapy Market Report areBluebird Bio, Sangamo, Spark Therapeutics, Dimension Therapeutics, Avalanche Bio, Celladon, Vical Inc., Advantagene.

Gene Therapymarket report provides a detailed analysis of global market size, regional and country-level market size, segmentation market growth, market share, competitive Landscape, sales analysis, the impact of domestic and global market players, value chain optimization, trade regulations, recent developments, opportunities analysis, strategic market growth analysis, product launches, area marketplace expanding, and technological innovations.

Market Segmentations: Global Gene Therapy market competition by top manufacturers, with production, price, revenue (value) and market share for each manufacturer.

Based on type, report split into Ex vivo, In Vivo.

Based on the end users/applications, this report focuses on the status and outlook for major applications/end users, consumption (sales), market share and growth rate for each application, including Cancer, Monogenic, Infectious disease, Cardiovascular disease, Other.

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The report introduces Gene Therapy basic information including definition, classification, application, industry chain structure, industry overview, policy analysis, and news analysis. Insightful predictions for the Gene Therapy Market for the coming few years have also been included in the report.

In the end, Gene Therapyreport provides details of competitive developments such as expansions, agreements, new product launches, and acquisitions in the market for forecasting, regional demand, and supply factor, investment, market dynamics including technical scenario, consumer behavior, and end-use industry trends and dynamics, capacity, spending were taken into consideration.

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Global Gene Therapy Market (2020-2026) | Latest COVID19 Impact Analysis | Know About Brand Players: Bluebird Bio, Sangamo, Spark Therapeutics,...

Honey bees have been celebrated by humans since they were first domesticated for pollination and honey production in the earliest days of human civilization. But honey bees are expendable we can purchase them from other countries, ship them overseas, and raise them in a non-native land to pollinate our crops. If all of the honey bees in the U.S. died today, wed buy more tomorrow. This World Bee Day, we should focus our celebration on the lesser-known species of amazing native bees that fill our environment.

Iridescent green sweat bee, called because it is known to be attracted to sweat

Via Wikimedia

World Bee Day was established by the United Nations to recognize the fundamental role of pollinators in pollination services, food production, and to safeguard biodiversity in the face of their many threats. It was not only in recognition of honey bees and the pollination services they provide, but of all bees. The proclamation specifically acknowledged and raised awareness of the urgent need to conserve all of the 20,000 species of native bees worldwide.

The blueberry bee, Osmia ribifloris, a blue-colored bee native to North America.

Via Wikimedia

Native bees are absolutely some of the coolest insects on earth. They come in a huge variety of shapes, sizes, and colors. Social species with a single queen like bumble bees make up about 10% of known bee species. Social bees live in nests and work together like honey bees to raise their young and forage for food. The other 90% are solitary species, meaning they live alone and are solely responsible for finding food and building a nest.

Stelis louisae, a red/orange carder bee

USGS

Native bees come in a variety of colors besides yellow and blackblue, green, orange, and red, to name a few. Some resemble wasps, as a defense mechanism for survival. Others are covered in tiny hairs, resembling giant teddy bears, or almost entirely hairless and smooth. Native bees are responsible for a majority of wild plant and crop pollination worldwide.

There are so many amazing native bees. Unfortunately, the focus generally lands on the domesticated workhorse Apis mellifera, instead of any one of the amazing native species. Native bees face a wide range of threats from lost habitat due to increasing development, lack of flowers for food, agricultural intensification, pesticides, and so much more. Honey bees actually pose a threat to native bees, introducing competition and spillover of diseases and parasites to native bees.

An all black bee, Dufourea monardae

Cole Cheng/USGS

There are a wide variety of studies in native bees, but educating the public is one of the best ways to encourage native bee conservation. So this World Bee Day, take some time to read up on pollinators, and learn what you can do to help our native bees.

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Deep-sea currents are spreading microplastics around the globe - Massive Science

Global Biologics Safety Testing Market Growth Projection

The Biologics Safety Testing market report [6 Years Forecast 2020-2026] focuses on the COVID19 Outbreak Impact analysis of key points influencing the growth of the market. The intelligence report prepared contains details on the leading players of the Global Biologics Safety Testing Market, along with various depending aspects related and associated with the market. Profile the Top Key Players of Biologics Safety Testing, with sales, revenue and global market share of Biologics Safety Testing are analyzed emphatically by landscape contrast and speak to info. Upstream raw materials and instrumentation and downstream demand analysis is additionally administrated. The Biologics Safety Testing market business development trends and selling channels square measure analyzed. Biologics Safety Testing industry research report enriched on worldwide competition by topmost prime manufactures which providing information such as Company Profiles, Gross, Gross Margin, Capacity, Product Picture and Specification, Production, Price, Cost, Revenue and contact information.

Biologics Safety Testing Market report provides in-depth review of the Expansion Drivers, Potential Challenges, Distinctive Trends, and Opportunities for market participants equip readers to totally comprehend the landscape of the Biologics Safety Testing market. Major prime key manufactures enclosed within the report alongside Market Share, Stock Determinations and Figures, Contact information, Sales, Capacity, Production, Price, Cost, Revenue and Business Profiles are (Lonza Group, Charles River, Merck, SGS, WuXi AppTec, Thermo Fisher Scientific, Sartorius, Cytovance Biologics, Pace Analytical Services, Toxikon). The main objective of the Biologics Safety Testing industry report is to Supply Key Insights on Competition Positioning, Current Trends, Market Potential, Growth Rates, and Alternative Relevant Statistics.

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There are 10 Chapters to deeply display the Biologics Safety Testing market:

Chapter 1, is executive summary of Biologics Safety Testing Market; Chapter 2, is definition and segment of Biologics Safety Testing; Chapter 3, to show info and data comparison of Biologics Safety Testing Players; Chapter 4, to explain the industry chain of Biologics Safety Testing; Chapter 5, to show comparison of regions and courtiers(or sub-regions); Chapter 6, to show competition and trade situation of Biologics Safety Testing Market; Chapter 7, to show comparison of applications; Chapter 8, to show comparison of types; Chapter 9, to show investment of Biologics Safety Testing Market; Chapter 10, to forecast Biologics Safety Testing market in the next years.

The Biologics Safety Testing market report provides a comprehensive analysis of: Industry overview, cost structure analysis, technical data and competitive analysis, topmost players analysis, development trend analysis, overall market overview, regional market analysis, consumers analysis and marketing type analysis.

Global Biologics Safety Testing Market report focuses on various key parameters that include:

Market concentration ratio Consumption growth rate Growth rate Turnover predictions Industry drivers and major challenges Recent market trends Geographical segmentation Competitive structure Competitive ranking analysis

Scope of Biologics Safety Testing Market:

The global Biologics Safety Testing market is valued at million US$ in 2019 and will reach million US$ by the end of 2026, growing at a CAGR of during 2020-2026. The objectives of this study are to define, segment, and project the size of the Biologics Safety Testing market based on company, product type, application and key regions.

This research report categorizes the global Biologics Safety Testing market by players/brands, region, type and application. This report also studies the global market status, competition landscape, market share, growth rate, future trends, market drivers, opportunities and challenges, sales channels, distributors, customers, research findings & conclusion, appendix & data source and Porters Five Forces Analysis.

On the basis on the end users/applications, this report focuses on the status and outlook for major applications/end users, shipments, revenue (Million USD), price, and market share and growth rate for each application.

Endotoxin Tests, Sterility Tests, Cell Line Authentication and Characterization Tests, Bioburden Tests, Cell Line Authentication, Residual Host Contaminant Detection Tests, Adventitious Agent Detection Tests, Others

On the basis of product type, this report displays the shipments, revenue (Million USD), price, and market share and growth rate of each type.

Vaccine Development, Blood Products Testing, Cellular & Gene Therapy, Tissue and Tissue-Related Products Testing, Stem Cell Research,

Market Size Segmentation by Region & Countries (Customizable):

North America

Europe

Asia-Pacific

South America

Center East and Africa

United States, Canada and Mexico

Germany, France, UK, Russia and Italy

China, Japan, Korea, India and Southeast Asia

Brazil, Argentina, Colombia

Saudi Arabia, UAE, Egypt, Nigeria and South Africa

Our exploration specialists acutely ascertain the significant aspects of the global Biologics Safety Testing market report. It also provides an in-depth valuation in regards to the future advancements relying on the past data and present circumstance of Biologics Safety Testing market situation. In this Biologics Safety Testing report, we have investigated the principals, players in the market, geological regions, product type, and market end-client applications. The global Biologics Safety Testing report comprises of primary and secondary data which is exemplified in the form of pie outlines, Biologics Safety Testing tables, analytical figures, and reference diagrams. The Biologics Safety Testing report is presented in an efficient way that involves basic dialect, basic Biologics Safety Testing outline, agreements, and certain facts as per solace and comprehension.

Important Features that are under offering & key highlights of the report:

Detailed overview of Biologics Safety Testing market Changing market dynamics of the industry In-depth market segmentation by Type, Application etc Historical, current and projected market size in terms of volume and value Recent industry trends and developments Competitive landscape of Biologics Safety Testing market Strategies of key players and product offerings Potential and niche segments/regions exhibiting promising growth A neutral perspective towards Biologics Safety Testing market performance Market players information to sustain and enhance their footprint

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Table of Content

1 Report Overview1.1 Study Scope1.2 Key Market Segments1.3 Players Covered1.4 Market Analysis by Type1.4.1 Global Biologics Safety Testing Market Size Growth Rate by Type (2014-2026)1.4.2 Major-Type1.4.3 Independent-Type1.4.4 Administrator-Type1.5 Market by Application1.5.1 Global Biologics Safety Testing Market Share by Application (2014-2026)1.5.2 Other1.6 Study Objectives1.7 Years Considered

2 Global Growth Trends2.1 Biologics Safety Testing Market Size2.2 Biologics Safety Testing Growth Trends by Regions2.2.1 Biologics Safety Testing Market Size by Regions (2014-2026)2.2.2 Biologics Safety Testing Market Share by Regions (2014-2020)2.3 Industry Trends2.3.1 Market Top Trends2.3.2 Market Drivers2.3.3 Market Opportunities

3 Market Share by Key Players3.1 Biologics Safety Testing Market Size by Manufacturers3.1.1 Global Biologics Safety Testing Revenue by Manufacturers (2014-2020)3.1.2 Global Biologics Safety Testing Revenue Market Share by Manufacturers (2014-2020)3.1.3 Global Biologics Safety Testing Market Concentration Ratio (CR5 and HHI)3.2 Biologics Safety Testing Key Players Head office and Area Served3.3 Key Players Biologics Safety Testing Product/Solution/Service3.4 Date of Enter into Biologics Safety Testing Market3.5 Mergers and Acquisitions, Expansion Plans

4 Breakdown Data by Type and Application4.1 Global Biologics Safety Testing Market Size by Type (2014-2020)4.2 Global Biologics Safety Testing Market Size by Application (2014-2020)

(5, 6, 7, 8, 9, 10, 11) United States, Europe,China,Japan,Southeast Asia,India,Central and South AmericaBiologics Safety Testing Market Size (2014-2020)Key PlayersBiologics Safety Testing Market Size by TypeBiologics Safety Testing Market Size by Application

12 International Players ProfilesCompany DetailsCompany Description and Business OverviewBiologics Safety Testing IntroductionRevenue in Biologics Safety Testing Business (2014-2020)Recent Development

13 Market Forecast 2020-202613.1 Market Size Forecast by Regions13.2 United States13.3 Europe13.4 China13.5 Japan13.6 Southeast Asia13.7 India13.8 Central and South America13.9 Market Size Forecast by Product (2020-2026)13.10 Market Size Forecast by Application (2020-2026)

14 Analysts Viewpoints/Conclusions

15 Appendix15.1 Research Methodology15.1.1 Methodology/Research Approach15.1.1.1 Research Programs/Design15.1.1.2 Market Size Estimation12.1.1.3 Market Breakdown and Data Triangulation15.1.2 Data Source15.1.2.1 Secondary Sources15.1.2.2 Primary Sources15.2 Disclaimer15.3 Author Details

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(2020-2026) Biologics Safety Testing Market Research, Growth Opportunities, Analysis and Forecasts Report - 3rd Watch News

Global Gene Therapy for Ovarian Cancer Market 2020 by Manufacturers, Countries, Type and Application, Forecast to 2025 is a fundamental and professional analysis of the essential elements driving the market growth rate and the revenue statistic. The report explains the global Gene Therapy for Ovarian Cancer industry growth structure and development trends. The report has administered several comprehensive elements including market share, supply chain, market trends, revenue graph, market size, and application spectrum. The report gives detailed information about major players comprising their name, company profile, product information. The report also highlights an accurate competitive overview of the business-driven outlook elaborating on expansion tactics adopted by major competitors of the industry.

The global Gene Therapy for Ovarian Cancer market is separated by company, by country, and by application/types for the competitive landscape analysis. Some crucial information related to the complete assessment that market retains has been given as well as the availability of several growth opportunities as been underlined. In this report, essential parameters such as development policies as well as plans, cost structures, supply and demand figures, gross margins, import or export consumption, revenue, and price are studied. Additionally, the document highlights the pricing of the product, production and consumption volume, cost analysis, industry value, barriers and growth drivers, major market players, demand and supply ratio of the market, the growth rate of the market and forecast from 2020 to 2025.

NOTE: Our final report will be revised to address COVID-19 effects on the specific market.

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Leading Players Analysis:

The global Gene Therapy for Ovarian Cancer industry report then covers global major leading industry players, providing information such as company profiles, product picture and specification, capacity, production, price, cost, revenue, and contact information. Upstream raw materials and equipment and downstream demand analysis are also carried out.

List of some major players from a wide list of coverage used under the bottom-up approach is: Takara Bio, VBL Therapeutics, CELSION, Targovax,

The product type of market such as: Intravenous, Intratumoral, Intraperitoneal

Applications of the market such as: Ovarian Cancer (unspecified), Recurrent Ovarian Epithelial Cancer, Platinum-Resistant Ovarian Cancer,

Major geographies mentioned in this report are as follows: North America (United States, Canada and Mexico), Europe (Germany, France, UK, Russia and Italy), Asia-Pacific (China, Japan, Korea, India and Southeast Asia), South America (Brazil, Argentina, Colombia etc.), Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria and South Africa)

Moreover, the study report has described the fundamental information about the global Gene Therapy for Ovarian Cancer market such as application, industry outlook, definition, market chain structure, policy analysis, classification and more. It also explains which product has the highest penetration in which market, profit margins, break-even analysis, and R&D status.

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Global Gene Therapy for Ovarian Cancer Market 2020 Significant Growth Prospects and COVID-19 Impact Analysis 2025 - Flagler Times

The UK is poised to lead the way as operators increase spending on North Sea decommissioning work amid low oil prices, according to a new report.

Independent research company Rystad Energy has predicted Britain is in line for nearly 80% of the 14billion it estimates could be spent on removal projects in north-west Europe over the next five years.

The researchers said that, with exploration and production budgets slashed since the Covid-19 pandemic took hold and sent oil prices tumbling and few profitable investment alternatives, operators are now likely to increase spending on decommissioning projects.

Rystad estimates the value for the market world-wide may reach 34.5billion by 2024.The report added that, with an average asset age of 25 years, the north-west European decommissioning sector could grow 20% in annual commitments over the next 18 months if the current low oil prices do not show signs of substantial recovery soon.

It continued: In addition to a rapidly maturing asset base and low oil prices that erode commercial viability and potential life extensions, the North Sea decommissioning market will also be helped by favourable service contract prices.

Rystad energy service analyst, Sumit Yadev, said: A protracted low price environment can potentially motivate operators to leverage low contract prices and commit to their asset retirement obligations, thus spurring decommissioning activity in the north-west Europe region.

This will also provide welcome opportunities for contractors in an otherwise gloomy oilfield services market.

The report warned increased spending on decommissioning may limit the room for operators to invest in other segments, including exploration, development and enhanced oil recovery initiatives.

Leading players such as Shell, Total, Repsol and Premier Oil are expected to assign 10% or more of their North Sea spending in the next five years to removal projects.

Only about 15% of North Sea assets have been decommissioned to date, but in its latest report, Rystad Energy predicts an average of 23 assets will cease production annually over the coming five years.

The research firm expects during the next decade operators will carry out the decommissioning of more than 2,500 wells in the sector, of which 1,500 are in the UK Continental Shelf (UKCS) area.

It said nearly 300,000 tonnes of topsides will be removed from the UKCS by 2025, along with almost 100,000 tonnes of substructure.

With around 50 topsides due to be decommissioned, Rystad estimated an average removal cost of more than 4,300 per tonne.

Plugging and abandonment (P&A) of wells is expected to make up about 45% of decommissioning costs over the next five years, followed by platform removals, which will account for nearly 20% of total expenditure.

Platform wells will be the dominant segment for P&A activity, making up about 65% of the total well abandonment, while the rest are subsea wells.

But, in cost terms, subsea wells will take the lead at an average of 9m each to abandon, compared to 4m for a platform well.

Some of the leading assets that will drive the North Sea decommissioning market include the Brent, Ninian and Thistle fields in the UK and Gyda, in Norway.

Shells Brent project would emerge as the single largest asset decommissioned globally, representing an outlay of nearly 2.5bn alone over the coming decade.

Rystad said the current low oil prices could play a pivotal role in boosting decommissioning spending in the UK if they persist beyond the end of this year.

Nearly 10% of all UK offshore assets have lifting costs above 20 per barrel, which will hamper their life extension prospects and make removal a better financial option if low prices continue.

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UK North Sea to dominate global decommissioning spend over next five years - News for the Oil and Gas Sector - Energy Voice

The global male hypogonadism market was valued at $2,594 million in 2015, and is estimated to reach $3,233 million by 2022, growing at a CAGR of 3.1% during the analysis period. Male hypogonadism is a medical condition characterized by the inability of the testes to produce sufficient amount of testosterone, which is responsible for the development of secondary sexual characteristics. This results in underdevelopment of muscles, impaired growth of body hair, development of breast tissues, and lack of deepening of the voice.

Some of the key players of Male Hypogonadism Market:AbbVie Inc., Allergan plc, Astrazeneca plc, Bayer AG., Eli Lilly and Company Ltd., Endo International plc., Merck & Co., Inc., Ferring, Finox Biotech, IBSA Institut Biochimque SA, Laboratoires Genevrier, Teva Pharmaceutical Industries Ltd.

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Male Hypogonadism Market report provides in-depth statistics and analysis available on the market status of the Male Hypogonadism key players and is a valuable method of obtaining guidance and direction for companies and business enterprise insider considering the Male Hypogonadism market. It contains the analysis of drivers, challenges, and restraints impacting the industry.

Type Segmentation:Klinefelters Syndrome

Kallmann Syndrome

Pituitary Disorders

Others

DRUG DELIVERY Segmentation:Topical Gels

Injectables

Transdermal Patches

Others

Major Regions play vital role in Male Hypogonadism market are:North America, Europe, China, Japan, Middle East & Africa, India, South America, Others

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Research objectives

To study and analyze the global Die Cutting Machines consumption (value & volume) by key regions/countries, type and application, history data, and forecast.

To understand the structure of Die Cutting Machines market by identifying its various subsegments.

Focuses on the key global Die Cutting Machines manufacturers, to define, describe and analyze the sales volume, value, market share, market competition landscape, SWOT analysis and development plans in next few years.

To analyze the Die Cutting Machines with respect to individual growth trends, future prospects, and their contribution to the total market.

To share detailed information about the key factors influencing the growth of the market (growth potential, opportunities, drivers, industry-specific challenges and risks).

To project the consumption of Die Cutting Machines submarkets, with respect to key regions (along with their respective key countries).

To analyze competitive developments such as expansions, agreements, new product launches, and acquisitions in the market.

To strategically profile the key players and comprehensively analyze their growth strategies.

Fundamentals of Table of Content:

Chapter 1 Executive Summary

Chapter 2 Abbreviation and Acronyms

Chapter 3 Preface

Chapter 4 Market Landscape

Chapter 5 Market Trend Analysis

Chapter 6 Industry Chain Analysis

Chapter 7 Latest Market Dynamics

Chapter 8 Trading Analysis

Chapter 9 Historical and Current Interposer in North America

Continue for TOC

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Demanded Report on Male Hypogonadism Market Analysis Forecast with Leading Key Players: AbbVie Inc., Allergan plc, Astrazeneca plc, Bayer AG., Eli...

Analysis of the Global Male Hypogonadism Market

A recently published market report on the Male Hypogonadism market highlights the pitfalls that companies might come across due to the unprecedented outbreak of COVID-19 (Coronavirus). Buyers can request comprehensive market analysis of Coronavirus and its impact on the Male Hypogonadism market to mitigate revenue losses.

This market research report on the Male Hypogonadism market published by Male Hypogonadism derives current insights about the competitive landscape of the Male Hypogonadism market. Further, the report unfolds detailed analysis of different segments of the Male Hypogonadism market and offers a thorough understanding of the growth potential of each market segment over the assessment period (20XX-20XX).

According to the analysts at Male Hypogonadism , the Male Hypogonadism market is predicted to register a CAGR growth of ~XX% during the assessment and reach a value of ~US$ XX by the end of 20XX. The report analyzes the micro and macro-economic factors that are projected to influence the growth of the Male Hypogonadism market in the coming decade.

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Key Insights Highlighted in the Report

Segmentation of the Male Hypogonadism Market

The presented report elaborate on the Male Hypogonadism market into different segments and ponders over the current and future business potentials of each segment. The report showcases the year-on-year growth of each segment and ponders upon the different factors that are likely to influence the growth of each market segment.

The various segments of the Male Hypogonadism market explained in the report include:

Key market playersMajor competitors identified in this market include Astrazeneca Plc., Merck & Co. Inc., Laboratories Genevrier, Allergan Plc., Endo International Plc., Ferring, AbbVie Inc., Eli Lilly and Company Ltd., Finox Biotech, Teva Pharmaceutical Industries Ltd., Bayer AG, IBSA Institut Biochimque, etc.

Based on the Region:Asia-Pacific (China, Japan, South Korea, India and ASEAN)North America (US and Canada)Europe (Germany, France, UK and Italy)Rest of World (Latin America, Middle East & Africa)

Based on the Type:Testosterone Replacement TherapyGonadotropin-Releasing Hormones Therapy

Based on the Application:Kallmann SyndromeKlinefelters SyndromePituitary DisordersOthers

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COVID-19: Responding to the business impacts of Global Male Hypogonadism Market : Current Trends and Future Estimations to Elucidate Imminent...

QY Research as of late produced a research report titled, Transdermal Testosterone . The research report speak about the potential development openings that exist in the worldwide market. The report is broken down on the basis of research procedures procured from historical and forecast information. The global Transdermal Testosterone market is relied upon to develop generously and flourish as far as volume and incentive during the gauge time frame. The report will give a knowledge about the development openings and controls that will build the market. Pursuers can increase important perception about the eventual fate of the market.

Key companies that are operating in the global Transdermal Testosterone market are: , AbbVie, Teva, Perrigo, Endo Pharmaceuticals, Acerus Pharmaceuticals, Lupin, Dr. Reddys Laboratories, Upsher-Smith Laboratories, Allergan, Cipla Inc.

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Segmental Analysis

The report incorporates significant sections, for example, type and end user and a variety of segments that decide the prospects of the market. Each type provide data with respect to the business esteem during the conjecture time frame. The application area likewise gives information by volume and consumption during the estimate time frame. The comprehension of this segment direct the readers in perceiving the significance of variables that shape the market development.

Global Transdermal Testosterone Market Segment By Type:

, Gel, Patch, Solution

Global Transdermal Testosterone Market Segment By Application:

, Primary hypogonadism, Hypogonadotropic hypogonadism, Late-onset hypogonadism

Competitive Landscape

The report incorporates various key players and producers working in the local and worldwide market. This segment shows the procedures received by players in the market to remain ahead in the challenge. New patterns and its reception by players assist readers with understanding the elements of the business and how it very well may be utilized to their own benefit. The readers can likewise recognize the strides of players to comprehend the global market better.

Key companies operating in the global Transdermal Testosterone market include , AbbVie, Teva, Perrigo, Endo Pharmaceuticals, Acerus Pharmaceuticals, Lupin, Dr. Reddys Laboratories, Upsher-Smith Laboratories, Allergan, Cipla Inc.

Key questions answered in the report:

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TOC

Table of Contents 1 Transdermal Testosterone Market Overview1.1 Transdermal Testosterone Product Overview1.2 Transdermal Testosterone Market Segment by Type1.2.1 Gel1.2.2 Patch1.2.3 Solution1.3 Global Transdermal Testosterone Market Size by Type (2015-2026)1.3.1 Global Transdermal Testosterone Market Size Overview by Type (2015-2026)1.3.2 Global Transdermal Testosterone Historic Market Size Review by Type (2015-2020)

1.3.2.1 Global Transdermal Testosterone Sales Market Share Breakdown by Type (2015-2026)

1.3.2.2 Global Transdermal Testosterone Revenue Market Share Breakdown by Type (2015-2026)

1.3.2.3 Global Transdermal Testosterone Average Selling Price (ASP) by Type (2015-2026)1.3.3 Global Transdermal Testosterone Market Size Forecast by Type (2021-2026)

1.3.3.1 Global Transdermal Testosterone Sales Market Share Breakdown by Application (2021-2026)

1.3.3.2 Global Transdermal Testosterone Revenue Market Share Breakdown by Application (2021-2026)

1.3.3.3 Global Transdermal Testosterone Average Selling Price (ASP) by Application (2021-2026)1.4 Key Regions Market Size Segment by Type (2015-2020)1.4.1 North America Transdermal Testosterone Sales Breakdown by Type (2015-2026)1.4.2 Europe Transdermal Testosterone Sales Breakdown by Type (2015-2026)1.4.3 Asia-Pacific Transdermal Testosterone Sales Breakdown by Type (2015-2026)1.4.4 Latin America Transdermal Testosterone Sales Breakdown by Type (2015-2026)1.4.5 Middle East and Africa Transdermal Testosterone Sales Breakdown by Type (2015-2026) 2 Global Transdermal Testosterone Market Competition by Company2.1 Global Top Players by Transdermal Testosterone Sales (2015-2020)2.2 Global Top Players by Transdermal Testosterone Revenue (2015-2020)2.3 Global Top Players Transdermal Testosterone Average Selling Price (ASP) (2015-2020)2.4 Global Top Manufacturers Transdermal Testosterone Manufacturing Base Distribution, Sales Area, Product Type2.5 Transdermal Testosterone Market Competitive Situation and Trends2.5.1 Transdermal Testosterone Market Concentration Rate (2015-2020)2.5.2 Global 5 and 10 Largest Manufacturers by Transdermal Testosterone Sales and Revenue in 20192.6 Global Top Manufacturers by Company Type (Tier 1, Tier 2 and Tier 3) (based on the Revenue in Transdermal Testosterone as of 2019)2.7 Date of Key Manufacturers Enter into Transdermal Testosterone Market2.8 Key Manufacturers Transdermal Testosterone Product Offered2.9 Mergers & Acquisitions, Expansion 3 Global Transdermal Testosterone Status and Outlook by Region (2015-2026)3.1 Global Transdermal Testosterone Market Size and CAGR by Region: 2015 VS 2020 VS 20263.2 Global Transdermal Testosterone Market Size Market Share by Region (2015-2020)3.2.1 Global Transdermal Testosterone Sales Market Share by Region (2015-2020)3.2.2 Global Transdermal Testosterone Revenue Market Share by Region (2015-2020)3.2.3 Global Transdermal Testosterone Sales, Revenue, Price and Gross Margin (2015-2020)3.3 Global Transdermal Testosterone Market Size Market Share by Region (2021-2026)3.3.1 Global Transdermal Testosterone Sales Market Share by Region (2021-2026)3.3.2 Global Transdermal Testosterone Revenue Market Share by Region (2021-2026)3.3.3 Global Transdermal Testosterone Sales, Revenue, Price and Gross Margin (2021-2026)3.4 North America Transdermal Testosterone Market Size YoY Growth (2015-2026)3.4.1 North America Transdermal Testosterone Revenue YoY Growth (2015-2026)3.4.2 North America Transdermal Testosterone Sales YoY Growth (2015-2026)3.5 Asia-Pacific Transdermal Testosterone Market Size YoY Growth (2015-2026)3.5.1 Asia-Pacific Transdermal Testosterone Revenue YoY Growth (2015-2026)3.5.2 Asia-Pacific Transdermal Testosterone Sales YoY Growth (2015-2026)3.6 Europe Transdermal Testosterone Market Size YoY Growth (2015-2026)3.6.1 Europe Transdermal Testosterone Revenue YoY Growth (2015-2026)3.6.2 Europe Transdermal Testosterone Sales YoY Growth (2015-2026)3.7 Latin America Transdermal Testosterone Market Size YoY Growth (2015-2026)3.7.1 Latin America Transdermal Testosterone Revenue YoY Growth (2015-2026)3.7.2 Latin America Transdermal Testosterone Sales YoY Growth (2015-2026)3.8 Middle East and Africa Transdermal Testosterone Market Size YoY Growth (2015-2026)3.8.1 Middle East and Africa Transdermal Testosterone Revenue YoY Growth (2015-2026)3.8.2 Middle East and Africa Transdermal Testosterone Sales YoY Growth (2015-2026) 4 Global Transdermal Testosterone by Application4.1 Transdermal Testosterone Segment by Application4.1.1 Primary hypogonadism4.1.2 Hypogonadotropic hypogonadism4.1.3 Late-onset hypogonadism4.2 Global Transdermal Testosterone Sales by Application: 2015 VS 2020 VS 20264.3 Global Transdermal Testosterone Historic Sales by Application (2015-2020)4.4 Global Transdermal Testosterone Forecasted Sales by Application (2021-2026)4.5 Key Regions Transdermal Testosterone Market Size by Application4.5.1 North America Transdermal Testosterone by Application4.5.2 Europe Transdermal Testosterone by Application4.5.3 Asia-Pacific Transdermal Testosterone by Application4.5.4 Latin America Transdermal Testosterone by Application4.5.5 Middle East and Africa Transdermal Testosterone by Application 5 North America Transdermal Testosterone Market Size by Country (2015-2026)5.1 North America Market Size Market Share by Country (2015-2020)5.1.1 North America Transdermal Testosterone Sales Market Share by Country (2015-2020)5.1.2 North America Transdermal Testosterone Revenue Market Share by Country (2015-2020)5.2 North America Market Size Market Share by Country (2021-2026)5.2.1 North America Transdermal Testosterone Sales Market Share by Country (2021-2026)5.2.2 North America Transdermal Testosterone Revenue Market Share by Country (2021-2026)5.3 North America Market Size YoY Growth by Country5.3.1 U.S. Transdermal Testosterone Market Size YoY Growth (2015-2026)5.3.2 Canada Transdermal Testosterone Market Size YoY Growth (2015-2026) 6 Europe Transdermal Testosterone Market Size by Country (2015-2026)6.1 Europe Market Size Market Share by Country (2015-2020)6.1.1 Europe Transdermal Testosterone Sales Market Share by Country (2015-2020)6.1.2 Europe Transdermal Testosterone Revenue Market Share by Country (2015-2020)6.2 Europe Market Size Market Share by Country (2021-2026)6.2.1 Europe Transdermal Testosterone Sales Market Share by Country (2021-2026)6.2.2 Europe Transdermal Testosterone Revenue Market Share by Country (2021-2026)6.3 Europe Market Size YoY Growth by Country6.3.1 Germany Transdermal Testosterone Market Size YoY Growth (2015-2026)6.3.2 France Transdermal Testosterone Market Size YoY Growth (2015-2026)6.3.3 U.K. Transdermal Testosterone Market Size YoY Growth (2015-2026)6.3.4 Italy Transdermal Testosterone Market Size YoY Growth (2015-2026)6.3.5 Russia Transdermal Testosterone Market Size YoY Growth (2015-2026) 7 Asia-Pacific Transdermal Testosterone Market Size by Country (2015-2026)7.1 Asia-Pacific Market Size Market Share by Country (2015-2020)7.1.1 Asia-Pacific Transdermal Testosterone Sales Market Share by Country (2015-2020)7.1.2 Asia-Pacific Transdermal Testosterone Revenue Market Share by Country (2015-2020)7.2 Asia-Pacific Market Size Market Share by Country (2021-2026)7.2.1 Asia-Pacific Transdermal Testosterone Sales Market Share by Country (2021-2026)7.2.2 Asia-Pacific Transdermal Testosterone Revenue Market Share by Country (2021-2026)7.3 Asia-Pacific Market Size YoY Growth by Country7.3.1 China Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.2 Japan Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.3 South Korea Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.4 India Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.5 Australia Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.6 Taiwan Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.7 Indonesia Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.8 Thailand Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.9 Malaysia Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.10 Philippines Transdermal Testosterone Market Size YoY Growth (2015-2026)7.3.11 Vietnam Transdermal Testosterone Market Size YoY Growth (2015-2026) 8 Latin America Transdermal Testosterone Market Size by Country (2015-2026)8.1 Latin America Market Size Market Share by Country (2015-2020)8.1.1 Latin America Transdermal Testosterone Sales Market Share by Country (2015-2020)8.1.2 Latin America Transdermal Testosterone Revenue Market Share by Country (2015-2020)8.2 Latin America Market Size Market Share by Country (2021-2026)8.2.1 Latin America Transdermal Testosterone Sales Market Share by Country (2021-2026)8.2.2 Latin America Transdermal Testosterone Revenue Market Share by Country (2021-2026)8.3 Latin America Market Size YoY Growth by Country8.3.1 Mexico Transdermal Testosterone Market Size YoY Growth (2015-2026)8.3.2 Brazil Transdermal Testosterone Market Size YoY Growth (2015-2026)8.3.3 Argentina Transdermal Testosterone Market Size YoY Growth (2015-2026) 9 Middle East and Africa Transdermal Testosterone Market Size by Country (2015-2026)9.1 Middle East and Africa Market Size Market Share by Country (2015-2020)9.1.1 Middle East and Africa Transdermal Testosterone Sales Market Share by Country (2015-2020)9.1.2 Middle East and Africa Transdermal Testosterone Revenue Market Share by Country (2015-2020)9.2 Middle East and Africa Market Size Market Share by Country (2021-2026)9.2.1 Middle East and Africa Transdermal Testosterone Sales Market Share by Country (2021-2026)9.2.2 Middle East and Africa Transdermal Testosterone Revenue Market Share by Country (2021-2026)9.3 Middle East and Africa Market Size YoY Growth by Country9.3.1 Turkey Transdermal Testosterone Market Size YoY Growth (2015-2026)9.3.2 Saudi Arabia Transdermal Testosterone Market Size YoY Growth (2015-2026)9.3.3 U.A.E Transdermal Testosterone Market Size YoY Growth (2015-2026) 10 Company Profiles and Key Figures in Transdermal Testosterone Business10.1 AbbVie10.1.1 AbbVie Corporation Information10.1.2 AbbVie Description, Business Overview and Total Revenue10.1.3 AbbVie Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.1.4 AbbVie Transdermal Testosterone Products Offered10.1.5 AbbVie Recent Development10.2 Teva10.2.1 Teva Corporation Information10.2.2 Teva Description, Business Overview and Total Revenue10.2.3 Teva Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.2.5 Teva Recent Development10.3 Perrigo10.3.1 Perrigo Corporation Information10.3.2 Perrigo Description, Business Overview and Total Revenue10.3.3 Perrigo Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.3.4 Perrigo Transdermal Testosterone Products Offered10.3.5 Perrigo Recent Development10.4 Endo Pharmaceuticals10.4.1 Endo Pharmaceuticals Corporation Information10.4.2 Endo Pharmaceuticals Description, Business Overview and Total Revenue10.4.3 Endo Pharmaceuticals Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.4.4 Endo Pharmaceuticals Transdermal Testosterone Products Offered10.4.5 Endo Pharmaceuticals Recent Development10.5 Acerus Pharmaceuticals10.5.1 Acerus Pharmaceuticals Corporation Information10.5.2 Acerus Pharmaceuticals Description, Business Overview and Total Revenue10.5.3 Acerus Pharmaceuticals Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.5.4 Acerus Pharmaceuticals Transdermal Testosterone Products Offered10.5.5 Acerus Pharmaceuticals Recent Development10.6 Lupin10.6.1 Lupin Corporation Information10.6.2 Lupin Description, Business Overview and Total Revenue10.6.3 Lupin Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.6.4 Lupin Transdermal Testosterone Products Offered10.6.5 Lupin Recent Development10.7 Dr. Reddys Laboratories10.7.1 Dr. Reddys Laboratories Corporation Information10.7.2 Dr. Reddys Laboratories Description, Business Overview and Total Revenue10.7.3 Dr. Reddys Laboratories Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.7.4 Dr. Reddys Laboratories Transdermal Testosterone Products Offered10.7.5 Dr. Reddys Laboratories Recent Development10.8 Upsher-Smith Laboratories10.8.1 Upsher-Smith Laboratories Corporation Information10.8.2 Upsher-Smith Laboratories Description, Business Overview and Total Revenue10.8.3 Upsher-Smith Laboratories Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.8.4 Upsher-Smith Laboratories Transdermal Testosterone Products Offered10.8.5 Upsher-Smith Laboratories Recent Development10.9 Allergan10.9.1 Allergan Corporation Information10.9.2 Allergan Description, Business Overview and Total Revenue10.9.3 Allergan Transdermal Testosterone Sales, Revenue and Gross Margin (2015-2020)10.9.4 Allergan Transdermal Testosterone Products Offered10.9.5 Allergan Recent Development10.10 Cipla Inc.10.10.1 Company Basic Information, Manufacturing Base and Competitors10.10.2 Transdermal Testosterone Product Category, Application and Specification10.10.3 Cipla Inc. Transdermal Testosterone Sales, Revenue, Price and Gross Margin (2015-2020)10.10.4 Main Business Overview10.10.5 Cipla Inc. Recent Development 11 Transdermal Testosterone Upstream, Opportunities, Challenges, Risks and Influences Factors Analysis11.1 Transdermal Testosterone Key Raw Materials11.1.1 Key Raw Materials11.1.2 Key Raw Materials Price11.1.3 Raw Materials Key Suppliers11.2 Manufacturing Cost Structure11.2.1 Raw Materials11.2.2 Labor Cost11.2.3 Manufacturing Expenses11.3 Transdermal Testosterone Industrial Chain Analysis11.4 Market Opportunities, Challenges, Risks and Influences Factors Analysis11.4.1 Market Opportunities and Drivers11.4.2 Market Challenges11.4.3 Market Risks11.4.4 Porters Five Forces Analysis 12 Market Strategy Analysis, Distributors12.1 Sales Channel12.2 Distributors12.3 Downstream Customers 13 Research Findings and Conclusion 14 Appendix14.1 Methodology/Research Approach14.1.1 Research Programs/Design14.1.2 Market Size Estimation14.1.3 Market Breakdown and Data Triangulation14.2 Data Source14.2.1 Secondary Sources14.2.2 Primary Sources14.3 Author Details14.4 Disclaimer

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Transdermal Testosterone Market Growth by Top Companies, Trends by Types and Application, Forecast to 2026| - Jewish Life News

DailyMailreports that a team of Canadian researchers have discovered a new sex hormone in zebrafish. They say this discovery could lead to developing better fertility treatment options for humans.

The researchers successfully restored partial sexual function in genetically mutated zebrafish with a single injection. In their trial, the jab was able to enhance further the ability of the female fish to ovulate and lay her eggs.

The fish possessed about 70% genes similar to humans, which makes it the perfect lab models. According to researchers, the key to the process is a small-like-molecule produced by the fish. Moreover, this molecule is found in other animals and humans as well.

According to Vance Trudeau, the senior author of the study, they mutated two related genes and analyzed their effects on the zebrafish's sexual function. Trudeau is a Professor of Neuroendocrinology at the University of Ottawa, Canada.

Additionally, he said that they used genetically modified fish to search for other factors that could improve sexual function. The researchers looked for clues leaning toward either increased spawning in cultured fish species or helping with the search for new infertility treatments for humans.

The findings of the research were published in Proceedings of the National Academy of Sciences.

Read Also: Men with Hypogonadism Leading to Low Testosterone Levels are More Likely to Die From the Coronavirus, Study Finds

Professor Trudeau and his co-author Kim Mitchell had discovered new functions that facilitate how males and females interact while mating when they initially started studying the effects of gene mutations in zebrafish.

Using gene technology developed at the Chinese Academy of Sciences, in Wuhan, China, the researchers were able to mutate two related genes under the name secretogranin-2. It encodes the protein with the same name.

Trudeau said that the first step of their experiments was to perform the gene editing to reduce the zebrafish's sexual behaviour. Furthermore, they changed the secretogranin-2 genes through specific mutations. The authors of the study found that it significantly affected the ability of females and males to breed.

According to Trudeau, it severely reduced their sexual behaviour. At first, the fish appeared normal. However, when both sexes were put together, they completely ignored each other. He explained how normally the male and female fish would engage in a 'courtship ritual' in which the male would chase the female.

Generally after the courtship, the female dispenses her eggs to the water, and the male fertilizes them. However, in a sample of gene-edited zebrafish couples used in the study, the researchers found only one in ten were able to spawn.

The experiments showed that the fish carrying the delivered mutations were capable of producing sperm and eggs, but were dreadful at mating. According to Trudeau, it was the first evidence that showed the mutation of genes leading to the disruption of sexual behaviour in animals.

For the experiment's second stage, the researchers used a fragment of secretogranin-2 in an attempt to reverse the seeming incapacity to mate. The team was able to partially restore sexual function by a single injection of the secretoneurin peptideinto the fish's body.

The researchers revealed new genes that can determine reproduction. Furthermore, the secretoneurin peptide itself has been classified as a new hormone with possible connotations for future fertility research.

According to Trudeau, the large secretogranin-2 genes could produce several other hormone-like peptides with functions still left to be discovered. He added that it would be exciting to explore the subject in future projects further.

Also Read: COVID-19 Male Patients to Receive Female Sex Hormones Estrogen and Progesterone To See if They Could Help Reduce Severity

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Scientists Discover New Sexual Hormone that Could Offer Better Fertility Treatments - Science Times