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Archive for the ‘IPS Cell Therapy’ Category

Introduction to Stem Cell Therapy – PubMed Central (PMC)

J Cardiovasc Nurs. Author manuscript; available in PMC 2014 Jul 21.

Published in final edited form as:

PMCID: PMC4104807

NIHMSID: NIHMS100185

1Department of Bioengineering, University of Illinois at Chicago

2Department of Physiology and Biophysics and Department of Bioengineering, University of Illinois at Chicago

1Department of Bioengineering, University of Illinois at Chicago

2Department of Physiology and Biophysics and Department of Bioengineering, University of Illinois at Chicago

Stem cells have the ability to differentiate into specific cell types. The two defining characteristics of a stem cell are perpetual self-renewal and the ability to differentiate into a specialized adult cell type. There are two major classes of stem cells: pluripotent that can become any cell in the adult body, and multipotent that are restricted to becoming a more limited population of cells. Cell sources, characteristics, differentiation and therapeutic applications are discussed. Stem cells have great potential in tissue regeneration and repair but much still needs to be learned about their biology, manipulation and safety before their full therapeutic potential can be achieved.

Stem cells have the ability to build every tissue in the human body, hence have great potential for future therapeutic uses in tissue regeneration and repair. In order for cells to fall under the definition of stem cells, they must display two essential characteristics. First, stem cells must have the ability of unlimited self-renewal to produce progeny exactly the same as the originating cell. This trait is also true of cancer cells that divide in an uncontrolled manner whereas stem cell division is highly regulated. Therefore, it is important to note the additional requirement for stem cells; they must be able to give rise to a specialized cell type that becomes part of the healthy animal.1

The general designation, stem cell encompasses many distinct cell types. Commonly, the modifiers, embryonic, and adult are used to distinguish stem cells by the developmental stage of the animal from which they come, but these terms are becoming insufficient as new research has discovered how to turn fully differentiated adult cells back into embryonic stem cells and, conversely, adult stem cells, more correctly termed somatic stem cells meaning from the body, are found in the fetus, placenta, umbilical cord blood and infants.2 Therefore, this review will sort stem cells into two categories based on their biologic properties - pluripotent stem cells and multipotent stem cells. Their sources, characteristics, differentiation and therapeutic applications are discussed.

Pluripotent stem cells are so named because they have the ability to differentiate into all cell types in the body. In natural development, pluripotent stem cells are only present for a very short period of time in the embryo before differentiating into the more specialized multipotent stem cells that eventually give rise to the specialized tissues of the body (). These more limited multipotent stem cells come in several subtypes: some can become only cells of a particular germ line (endoderm, mesoderm, ectoderm) and others, only cells of a particular tissue. In other words, pluripotent cells can eventually become any cell of the body by differentiating into multipotent stem cells that themselves go through a series of divisions into even more restricted specialized cells.

During natural embryo development, cells undergo proliferation and specialization from the fertilized egg, to the blastocyst, to the gastrula during natural embryo development (left side of panel). Pluripotent, embryonic stem cells are derived from the inner cell mass of the blastoctyst (lightly shaded). Multipotent stem cells (diamond pattern, diagonal lines, and darker shade) are found in the developing gastrula or derived from pluripotent stem cells and are restricted to give rise to only cells of their respective germ layer.

Based on the two defining characteristics of stem cells (unlimited self-renewal and ability to differentiate), they can be described as having four outcomes or fates3 (). A common fate for multipotent stem cells is to remain quiescent without dividing or differentiating, thus maintaining its place in the stem cell pool. An example of this is stem cells in the bone marrow that await activating signals from the body. A second fate of stem cells is symmetric self-renewal in which two daughter stem cells, exactly like the parent cell, arise from cell division. This does not result in differentiated progeny but does increase the pool of stem cells from which specialized cells can develop in subsequent divisions. The third fate, asymmetric self-renewal, occurs when a stem cell divides into two daughter cells, one a copy of the parent, the other a more specialized cell, named a somatic or progenitor cell. Asymmetric self-renewal results in the generation of differentiated progeny needed for natural tissue development/regeneration while also maintaining the stem cell pool for the future. The fourth fate is that in which a stem cell divides to produce two daughters both different from the parent cell. This results in greater proliferation of differentiated progeny with a net loss in the stem cell pool.

Four potential outcomes of stem cells. A) Quiescence in which a stem cell does not divide but maintains the stem cell pool. B) Symmetric self-renewal where a stem cell divides into two daughter stem cells increasing the stem cell pool. C) Asymmetric self-renewal in which a stem cell divides into one differentiated daughter cell and one stem cell, maintaining the stem cell pool. D) Symmetric division without self-renewal where there is a loss in the stem cell pool but results in two differentiated daughter cells. (SC- Stem cell, DP-Differentiated progeny)

The factors that determine the fate of stem cells is the focus of intense research. Knowledge of the details could be clinically useful. For example, clinicians and scientists might direct a stem cell population to expand several fold through symmetrical self-renewal before differentiation into multipotent or more specialized progenitor cells. This would ensure a large, homogeneous population of cells at a useful differentiation stage that could be delivered to patients for successful tissue regeneration.

Pluripotent stem cells being used in research today mainly come from embryos, hence the name, embryonic stem cells. Pre-implantation embryos a few days old contain only 10-15% pluripotent cells in the inner cell mass (). Those pluripotent cells can be isolated, then cultured on a layer of feeder cells which provide unknown cues for many rounds of proliferation while sustaining their pluripotency.

Recently, two different groups of scientists induced adult cells back into the pluripotent state by molecular manipulation to yield induced pluripotent stem cells (iPS) that share some of the same characteristics as embryonic stem cells such as proliferation, morphology and gene expression (in the form of distinct surface markers and proteins being expressed).4-8 Both groups used retroviruses to carry genes for transcription factors into the adult cells. These genes are transcribed and translated into proteins that regulate the expression of other genes designed to reprogram the adult nucleus back into its embryonic state. Both introduced the embryonic transcription factors known as Sox2 and Oct4. One group also added Klf4 and c-Myc4, and the other group added Lin28 and Nanog.6 Other combinations of factors would probably also work, but, unfortunately, neither the retroviral carrier method nor the use of the oncogenic transcription factor c-Myc are likely to be approved for human therapy. Consequently, a purely chemical approach to deliver genes into the cells, and safer transcription factors are being tried. Results of these experiments look promising.9

Multipotent stem cells may be a viable option for clinical use. These cells have the plasticity to become all the progenitor cells for a particular germ layer or can be restricted to become only one or two specialized cell types of a particular tissue. The multipotent stem cells with the highest differentiating potential are found in the developing embryo during gastrulation (day 14-15 in humans, day 6.5-7 in mice). These cells give rise to all cells of their particular germ layer, thus, they still have flexibility in their differentiation capacity. They are not pluripotent stem cells because they have lost the ability to become cells of all three germ layers (). On the low end of the plasticity spectrum are the unipotent cells that can become only one specialized cell type such as skin stem cells or muscle stem cells. These stem cells are typically found within their organ and although their differentiation capacity is restricted, these limited progenitor cells play a vital role in maintaining tissue integrity by replenishing aging or injured cells. There are many other sub-types of multipotent stem cells occupying a range of differentiation capacities. For example, multipotent cells derived from the mesoderm of the gastrula undergo a differentiation step limiting them to muscle and connective tissue; however, further differentiation results in increased specialization towards only connective tissue and so on until the cells can give rise to only cartilage or only bone.

Multipotent stem cells found in bone marrow are best known, because these have been used therapeutically since the 1960s10 (their potential will be discussed in greater detail in a later section). Recent research has found new sources for multipotent stem cells of greater plasticity such as the placenta and umbilical cord blood.11 Further, the heart, until recently considered void of stem cells, is now known to contain stem cells with the potential to become cardiac myocytes.12 Similarly, neuro-progenitor cells have been found within the brain.13

The cardiac stem cells are present in such small numbers, that they are difficult to study and their function has not been fully determined. The second review in this series will discuss their potential in greater detail.

Since Federal funding for human embryonic stem cells is restricted in the United States, many scientists use the mouse model instead. Besides their ability to self-renew indefinitely and differentiate into cell types of all three germ layers, murine and human pluripotent stem cells have much in common. It should not be surprising that so many pluripotency traits are conserved between species given the shared genomic sequences and intra-cellular structure in mammals. Both mouse and human cells proliferate indefinitely in culture, have a high nucleus to cytoplasm ratio, need the support of growth factors derived from other live cells, and display similar surface antigens, transcription factors and enzymatic activity (i.e. high alkaline phosphatase activity).14 However, differences between mouse and human pluripotent cells, while subtle, are very important. Although the transcription factors mentioned above to induce pluripotency from adult cells (Oct3/4 and Sox2) are shared, the extracellular signals needed to regulate them differ. Mouse embryonic stem cells need the leukemia inhibitory factor and bone morphogenic proteins while human require the signaling proteins Noggin and Wnt for sustained pluripotency.15 Surface markers used to identify pluripotent cells also differ slightly between the two species as seen in the variants of the adhesion molecule SSEA (SSEA-1 in mouse, SSEA-3 & 4 in humans).16 Thus, while pluripotency research in mouse cells is valuable, a direct correlation to the human therapy is not likely.

Last, but certainly not least, a big difference between mouse and human stem cells are the moral and ethical dilemmas that accompany the research. Some people consider working with human embryonic stem cells to be ethically problematic while very few people have reservations on working with the mouse models. However, given the biological differences between human and mouse cells, most scientists believe that data relevant for human therapy will be missed by working only on rodents.

Cell surface markers are typically also used to identify multipotent stem cells. For example, mesenchymal stem cells can be purified from the whole bone marrow aspirate by eliminating cells that express markers of committed cell types, a step referred to as lineage negative enrichment, and then further separating the cells that express the sca-1 and c-Kit surface markers signifying mesenchymal stem cells. Both the lineage negative enrichment step and the sca-1/c-Kit isolation can be achieved by using flow cytometry and is discussed in further detail in the following review. The c-Kit surface marker also is used to distinguish the recently discovered cardiac stem cells from the rest of the myocardium. A great deal of recent work in cardiovascular research has centered on trying to find which markers indicate early multipotent cells that will give rise to pre-cardiac myocytes. Cells with the specific mesodermal marker, Kdr, give rise to the progenitor cells of the cardiovascular system including contracting cardiac myocytes, endothelial cells and vascular smooth muscle cells and are therefore considered to be the earliest cells with specification towards the cardiovascular lineage.17 Cells at this early stage still proliferate readily and yet are destined to become cells of the cardiovascular system and so may be of great value therapeutically.

Scientists are still struggling to reliably direct differentiation of stem cells into specific cell types. They have used a virtual alphabet soup of incubation factors toward that end (including trying a variety of growth factors, chemicals and complex substrates on which the cells are grown), with, so far, only moderate success. As an example of this complexity, one such approach to achieve differentiation towards cardiac myocytes is to use the chemical activin A and the growth factor BMP-4. When these two factors are administered to pluripotent stem cells in a strictly controlled manner, both in concentration and temporally, increased efficiency is seen in differentiation towards cardiac myocytes, but still, only 30% of cells can be expected to become cardiac.18

Multipotent cells have also been used as the starting point for cell therapy, again with cocktails of growth factors and/or chemicals to induce differentiation toward a specific, desired lineage. Some recipes are simple, such as the use of retinoic acid to induce mesenchymal stem cells into neuronal cells,19 or transforming growth factor- to make bone marrow-derived stem cells express cardiac myocyte markers.20 Others are complicated or ill-defined such as addition of the unknown factors secreted by cells in culture. Physical as well as chemical cues cause differentiation of stem cells. Simply altering the stiffness of the substrate on which cells are cultured can direct stem cells to neuronal, myogenic or osteogenic lineages.21 Cells evolve in physical and chemical environments so a combination of both will probably be necessary for optimal differentiation of stem cells. The importance of physical cues in the cells environment will be discussed in greater detail in the final review of this series. Ideally, for stem cells to be used therapeutically, efficient, uniform protocols must be established so that cells are a well-controlled and well-defined entity.

Pluripotent stem cells have not yet been used therapeutically in humans because many of the early animal studies resulted in the undesirable formation of unusual solid tumors, called teratomas. Teratomas are made of a mix of cell types from all the early germ layers. Later successful animal studies used pluripotent cells modified to a more mature phenotype which limits this proliferative capacity. Cells derived from pluripotent cells have been used to successfully treat animals. For example, animals with diabetes have been treated by the creation of insulin-producing cells responsive to glucose levels. Also, animals with acute spinal cord injury or visual impairment have been treated by creation of new myelinated neurons or retinal epithelial cells, respectively. Commercial companies are currently in negotiations with the FDA regarding the possibility of advancing to human trials. Other animal studies have been conducted to treat several maladies such as Parkinsons disease, muscular dystrophy and heart failure.18,22,23

Scientists hope that stem cell therapy can improve cardiac function by integration of newly formed beating cardiac myocytes into the myocardium to produce greater force. Patches of cardiac myocytes derived from human embryonic stem cells can form viable human myocardium after transplantation into animals,24 with some showing evidence of electrical integration.25,26 Damaged rodent hearts showed slightly improved cardiac function after injection of cardiac myocytes derived from human embryonic stem cells.21 The mechanisms for the gain in function are not fully understood but it may be only partially due to direct integration of new beating heart cells. It is more likely due to paracrine effects that benefit other existing heart cells (see next review).

Multipotent stem cells harvested from bone marrow have been used since the 1960s to treat leukemia, myeloma and lymphoma. Since cells there give rise to lymphocytes, megakaryocytes and erythrocytes, the value of these cells is easily understood in treating blood cancers. Recently, some progress has been reported in the use of cells derived from bone marrow to treat other diseases. For example, the ability to form whole joints in mouse models27 has been achieved starting with mesenchymal stem cells that give rise to bone and cartilage. In the near future multipotent stem cells are likely to benefit many other diseases and clinical conditions. Bone marrow-derived stem cells are in clinical trials to remedy heart ailments. This is discussed in detail in the next review of this series.

Pluripotent and multipotent stem cells have their respective advantages and disadvantages. The capacity of pluripotent cells to become any cell type is an obvious therapeutic advantage over their multipotent kin. Theoretically, they could be used to treat diseased or aging tissues in which multipotent stem cells are insufficient. Also, pluripotent stem cells proliferate more rapidly so can yield higher numbers of useful cells. However, use of donor pluripotent stem cells would require immune suppressive drugs for the duration of the graft28 while use of autologous multipotent stem cells (stem cells from ones self) would not. This ability to use ones own cells is a great advantage of multipotent stem cells. The immune system recognizes specific surface proteins on cells/objects that tell them whether the cell is from the host and is healthy. Autologous, multipotent stem cells have the patients specific surface proteins that allow it to be accepted by the hosts immune system and avoid an immunological reaction. Pluripotent stem cells, on the other hand, are not from the host and therefore, lack the proper signals required to stave off rejection from the immune system. Research is ongoing trying to limit the immune response caused by pluripotent cells and is one possible advantage that iPS cells may have.

The promises of cures for human ailments by stem cells have been much touted but many obstacles must still be overcome. First, more human pluripotent and multipotent cell research is needed since stem cell biology differs in mice and men. Second, the common feature of unlimited cell division shared by cancer cells and pluripotent stem cells must be better understood in order to avoid cancer formation. Third, the ability to acquire large numbers of the right cells at the right stage of differentiation must be mastered. Fourth, specific protocols must be developed to enhance production, survival and integration of transplanted cells. Finally, clinical trials must be completed to assure safety and efficacy of the stem cell therapy. When it comes to stem cells, knowing they exist is a long way from using them therapeutically.

Supported by NIH (HL 62426 and T32 HL 007692)

Link:
Introduction to Stem Cell Therapy - PubMed Central (PMC)

Stem cells: Therapy, controversy, and research

Researchers have been looking for something that can help the body heal itself. Although studies are ongoing, stem cell research brings this notion of regenerative medicine a step closer. However, many of its ideas and concepts remain controversial. So, what are stem cells, and why are they so important?

Stem cells are cells that can develop into other types of cells. For example, they can become muscle or brain cells. They can also renew themselves by dividing, even after they have been inactive for a long time.

Stem cell research is helping scientists understand how an organism develops from a single cell and how healthy cells could be useful in replacing cells that are not working correctly in people and animals.

Researchers are now studying stem cells to see if they could help treat a variety of conditions that impact different body systems and parts.

This article looks at types of stem cells, their potential uses, and some ethical concerns about their use.

The human body requires many different types of cells to function, but it does not produce every cell type fully formed and ready to use.

Scientists call a stem cell an undifferentiated cell because it can become any cell. In contrast, a blood cell, for example, is a differentiated cell because it has already formed into a specific kind of cell.

The sections below look at some types of stem cells in more detail.

Scientists extract embryonic stem cells from unused embryos left over from in vitro fertilization procedures. They do this by taking the cells from the embryos at the blastocyst stage, which is the phase in development before the embryo implants in the uterus.

These cells are undifferentiated cells that divide and replicate. However, they are also able to differentiate into specific types of cells.

There are two main types of adult stem cells: those in developed bodily tissues and induced pluripotent stem (iPS) cells.

Developed bodily tissues such as organs, muscles, skin, and bone include some stem cells. These cells can typically become differentiated cells based on where they exist. For example, a brain stem cell can only become a brain cell.

On the other hand, scientists manipulate iPS cells to make them behave more like embryonic stem cells for use in regenerative medicine. After collecting the stem cells, scientists usually store them in liquid nitrogen for future use. However, researchers have not yet been able to turn these cells into any kind of bodily cell.

Scientists are researching how to use stem cells to regenerate or treat the human body.

The list of conditions that stem cell therapy could help treat may be endless. Among other things, it could include conditions such as Alzheimers disease, heart disease, diabetes, and rheumatoid arthritis. Doctors may also be able to use stem cells to treat injuries in the spinal cord or other parts of the body.

They may do this in several ways, including the following.

In some tissues, stem cells play an essential role in regeneration, as they can divide easily to replace dead cells. Scientists believe that knowing how stem cells work can help treat damaged tissue.

For instance, if someones heart contains damaged tissue, doctors might be able to stimulate healthy tissue to grow by transplanting laboratory-grown stem cells into the persons heart. This could cause the heart tissue to renew itself.

One study suggested that people with heart failure showed some improvement 2 years after a single-dose administration of stem cell therapy. However, the effect of stem cell therapy on the heart is still not fully clear, and research is still ongoing.

Another investigation suggested that stem cell therapies could be the basis of personalized diabetes treatment. In mice and laboratory-grown cultures, researchers successfully produced insulin-secreting cells from stem cells derived from the skin of people with type 1 diabetes.

Study author Jeffrey R. Millman an assistant professor of medicine and biomedical engineering at the Washington University School of Medicine in St. Louis, MO said, What were envisioning is an outpatient procedure in which some sort of device filled with the cells would be placed just beneath the skin.

Millman hopes that these stem cell-derived beta cells could be ready for research in humans within 35 years.

Stem cells could also have vast potential in developing other new therapies.

Another way that scientists could use stem cells is in developing and testing new drugs.

The type of stem cell that scientists commonly use for this purpose is the iPS cell. These are cells that have already undergone differentiation but which scientists have genetically reprogrammed using genetic manipulation, sometimes using viruses.

In theory, this allows iPS cells to divide and become any cell. In this way, they could act like undifferentiated stem cells.

For example, scientists want to grow differentiated cells from iPS cells to resemble cancer cells and use them to test anticancer drugs. This could be possible because conditions such as cancer, as well as some congenital disabilities, happen because cells divide abnormally.

However, more research is taking place to determine whether or not scientists really can turn iPS cells into any kind of differentiated cell and how they can use this process to help treat these conditions.

In recent years, clinics have opened that offer different types of stem cell treatments. One 2016 study counted 570 of these clinics in the United States alone. They appear to offer stem cell-based therapies for conditions ranging from sports injuries to cancer.

However, most stem cell therapies are still theoretical rather than evidence-based. For example, researchers are studying how to use stem cells from amniotic fluid which experts can save after an amniocentesis test to treat various conditions.

The Food and Drug Administration (FDA) does allow clinics to inject people with their own stem cells as long as the cells are intended to perform only their normal function.

Aside from that, however, the FDA has only approved the use of blood-forming stem cells known as hematopoietic progenitor cells. Doctors derive these from umbilical cord blood and use them to treat conditions that affect the production of blood. Currently, for example, a doctor can preserve blood from an umbilical cord after a babys birth to save for this purpose in the future.

The FDA lists specific approved stem cell products, such as cord blood, and the medical facilities that use them on its website. It also warns people to be wary of undergoing any unproven treatments because very few stem cell treatments have actually reached the earliest phase of a clinical trial.

Historically, the use of stem cells in medical research has been controversial. This is because when the therapeutic use of stem cells first came to the publics attention in the late 1990s, scientists were only deriving human stem cells from embryos.

Many people disagree with using human embryonic cells for medical research because extracting them means destroying the embryo. This creates complex issues, as people have different beliefs about what constitutes the start of human life.

For some people, life starts when a baby is born, while for others, it starts when an embryo develops into a fetus. Meanwhile, other people believe that human life begins at conception, so an embryo has the same moral status and rights as a human child.

Former U.S. president George W. Bush had strong antiabortion views. He believed that an embryo should be considered a life and not be used for scientific experiments. Bush banned government funding for human stem cell research in 2001, but former U.S. president Barack Obama then revoked this order. Former U.S. president Donald Trump and current U.S. president Joe Biden have also gone back and forth with legislation on this.

However, by 2006, researchers had already started using iPS cells. Scientists do not derive these stem cells from embryonic stem cells. As a result, this technique does not have the same ethical concerns. With this and other recent advances in stem cell technology, attitudes toward stem cell research are slowly beginning to change.

However, other concerns related to using iPS cells still exist. This includes ensuring that donors of biological material give proper consent to have iPS cells extracted and carefully designing any clinical studies.

Researchers also have some concerns that manipulating these cells as part of stem cell therapy could lead to the growth of cancerous tumors.

Although scientists need to do much more research before stem cell therapies can become part of regular medical practice, the science around stem cells is developing all the time.

Scientists still conduct embryonic stem cell research, but research into iPS cells could help reduce some of the ethical concerns around regenerative medicine. This could lead to much more personalized treatment for many conditions and the ability to regenerate parts of the human body.

Learn more about stem cells, where they come from, and their possible uses here.

Read this article:
Stem cells: Therapy, controversy, and research

How much does stem cell therapy cost in 2021? – The Niche

One of the most common questions Ive gotten over the last decade is, how much does stem cell therapy cost? They actually seem most often to want to know more specifically how much itshould cost.

To try to authoritatively answer this now in 2021 we need data from the present and past along with expert perspectives.

These kinds of questions on what are common and reasonable prices have continued in 2021. However, the types of queries have also evolved as things have gotten more complicated. There are many layers to the question of cost, which I cover here in todays article. In the big picture, the most worrisome potential cost is to your health if you proceed with unproven stem cell injections.

Stem cell cost questions | Stem cells cost $2,500 to $20,000| Why do stem cells cost so much? | How have stem cell prices changed? | Stem cell supplement cost | FTC actions and patients as consumers | Does insurance or Medicare cover stem cell therapy? | Patient fundraising | Looking ahead will stem cell costs go down?| References

This post is the most comprehensive look at stem cell treatment cost and costs of related therapies that Ive seen on the web, especially factoring in our inclusion of historical polling data from past years here on The Niche. The above bullet point list is what is covered in todays post and you can jump to sections that interest you most by clicking on those table of contents bullet points.

You can also watch the video I made summarizing the key points of this post below.

Furthermore, it encompasses other important issues related to insurance, fundraising, and approaches to being a smart consumer. Keep in mind that almost all stem cell therapies outside the bone marrow/hematopoietic sphere are not FDA-approved. They mostly lack rigorous data to back them up too. So this post is definitely not recommending you get them. I advise against it, but many people still want info on cost.

Lets get started.

After more than a decade of blogging about stem cells from just about every angle, its interesting to consider trends in the types of questions I get asked. Beyond cost, I also often get asked How much of a stem cell treatment price does insurance cover?

Of course, insurance (or lack thereof) directly bears on cost too. Ill get more into insurance later in the post.

In a way its not so surprising that cost is so much on peoples minds now for a few reasons.

First, as compared to many years back, people now view stem cell injections as a more everyday thing. Stem cell therapy is often available just down the street at a local strip mall.

Back in 2010 and in the 5 or so years after that, people instead more often viewed stem cells as some amazing thing out of reach to them at that time. Now people view stem cell offerings through the lens of consumers.

Sadly, another major part of the reason for the change in perceptions of stem cell treatments is the tidal wave of stem cell clinics from coast to coast in the US selling unproven and sometimes dangerous offerings.

At the same time, some universities and large medical centers also sell stem cell or similar offerings that arent proven. Im worried that that number may be increasing too and patients who may be paying there for unproven stem cells way at the very high end of the cost spectrum, sometimes above $100K.

Other stem cell suppliers and clinics market stem cell-related stuff that isnt real stem cells such as platelet rich plasma or PRP (see my comprehensive guide to PRP including a helpful infographic here) or injections of often dead perinatal stem cell products.

For all these reasons about once every year or two, I do polling asking the readers of The Niche here about their experiences.

Ive done the polling again now in 2020 in a more comprehensive form.

To have a sense of cost, we need to ask patients certain questions. How much did you pay per injection? How many injections did you get? Where did you get them?

Keep in mind that the total cost of stem cell therapy is the product of the cost per injection times the # of injections. For instance, if a stem cell injection costs $8,000 and you get 10 injections, your total cost is $80,000.

Unfortunately, the unproven stem cell clinics generally do not volunteer data on how much they charge. They also often encourage patients to get many injections.

Our 2020 polling data (you can still participate and I will update this) for stem cell treatments are in the graphic above. Here are some highlights.

The self-reported responses on cost for stem cell treatments, as indicated by respondents to our 2020 polling, suggest the price has gone up.

While the most common answer in 2019 was $2,501-$5,000, in 2020 the most common response was $10,001-$20,000, while $2,501-$5,000 was close behind.

The percentage of people paying the most, more than $100,000, was only slightly (probably non-significantly) higher in 2020, but both in 2019 and 2020 the percentage of people paying over $100K was much higher than in 2018 polling.

Keep in mind this is the cost per injection so how many injections do patients typically get? While the number of injections reported most commonly was 1 in both 2019 and 2020, in 2020, the second most common answer was 6-10 injections, a big boost from 2019. Again, more injections end up multiplying things up to boost the total cost. Only a few people in the polling had many injections, but in my view it is still striking to see anyone say theyve received more than 20 stem cell injections.

For comparison, the 2019 polling can be found here, but some of the key results are captured in a combo screenshot Ive included here. I got a lot more responses to the polling in 2019 so that makes me more confident in the data than in the 2020 polling so far, but I hope well get more responses moving forward in 2020 and if we do, again Ill update the info in this post.

What you can see from 2019 is that a plurality of respondents reported getting one stem cell injection, but 60% of people nonetheless got more than one stem cell injection.

Remarkably about 1 in 20-25 people received more than 20 stem cell injections.

About another 1 in 20 people got 6-20 injections. I find this amount of repeat injections to be surprising and concerning as it amplifies health and financial risks.

In terms of cost per injection, the results are pretty similar to 2018 (see at right below) on the whole.

This kind of polling isnt super scientific, but can gauge trends. Unfortunately, I havent really seen much other published data on stem cell clinic costs in actual journals.

I dont know if its noise or not, but the percentage of people paying over $100K is about 2-fold higher in 2019 versus 2018.

There are more people may be paying $10K-$20K as well now in 2020 vs. 2019 or 2018.

There is growing interest from the public in stem cell supplements. I did a post on this earlier in 2020 so take a look here, which was essentially a review of stem cell supplements like Regenokine. In terms of cost, while supplements are far less expensive than getting stem cell, PRP, or exosome injections, supplements are still pricey for what you get. Its not unusual to pay $100 for a small bottle of stem cell supplements, the other factor to consider is that these supplements generally have no solid, published data behind them so you might as well be paying $100 for water. Its unclear what risks taking these supplements might bring as well.

On the economic side, you might think that the feds like the FTC would be actively pursuing false or even fraudulent marketing of stem cells via the web and other kinds of advertising, but in total so far the FTC to my knowledge has only taken relatively few actions such as this one. and then some letters for COVID-related marketing of stem cells and other biologics earlier this year in 2020.

Oddly, there were just that a couple blips of FTC activity, especially considering the sea of questionable stem cell clinic-related ads out there. This ranges from major newspapers to inflight magazines to mobile ads on a stem-cell-mobile to television. Then of course there are the infomercial seminars.

Patients should also view themselves as consumers. Savvy customers considering paying money to stem cell clinics should do their homework. I often tell patients to use at a minimum the kinds of tough standards they bring to the car-buying process. Over the last few years Consumer Reports has been interested in the stem cell treatment world and done some reporting that is worth reading.

A common question I hear is the following: is stem cell therapy covered by insurance? Unfortunately for patients desperate to try stem cells, insurance generally does not provide any coverage, which often leads them to take extreme financial measures. These steps can include fundraising (more below).

In my view, the Regenexx brand has made a big deal out of how some employers contribute towards costs of their clinics offerings. Im not so clear on where that stands today in 2020.

Does Medicare cover stem cell therapies? Medicare will generally cover the cost of established bone marrow transplantation type therapies. However it does not cover unproven stem cell therapies.

Patients are often reaching out to me so I know that many of them have gone to extraordinary measures to raise the money to pay to unproven stem cell clinics. Its painful to think about what little they get in return. Since we are by definition talking about unproven medical procedures here, in my view this money is largely down the drain.

If you have other data on stem cell economic issues such as what patients pay please let me know. Then theres the issue of what it actually costs the clinics per injection and in turn: whats their profit margin?

What ends up happening is that patients take out second mortgages on their houses, try to collect funds from friends and relatives, or turn to online fundraising. The internet fundraising efforts most often end up on GoFundMe. This is a trend Ive been noticing for years. Some colleagues even published a paper on this trend, a very interesting and an important read. The paper is Crowdfunding for Unproven Stem CellBased Interventions in JAMA by Jeremy Snyder,Leigh Turner , and Valorie A. Crooks. Heres a key passage:

As of December 3, 2017, our search identified 408 campaigns (GoFundMe=358; YouCaring=50) seeking donations for stem cell interventions advertised by 50 individual businesses. These campaigns requested $7439308 and received pledges for $1450011 from 13050 donors. The campaigns were shared 111044 times on social media. Two campaigns were duplicated across platforms but shared separately on social media. Of the 408 campaigns, 178 (43.6%) made statements that were definitive or certain about the interventions efficacy, 124 (30.4%) made statements optimistic or hopeful about efficacy, 63 (15.4%) made statements of both kinds, and 43 (10.5%) did not make efficacy claims. All mentions of risks (n=36) claimed the intervention had low/no risks compared with alternative treatments.

Supposedly GoFundMe has taken some steps to lower the often ethically thorny stem cell fundraising on its site, but Im not sure how much it has changed.

There is pressure on stem cell clinics now in 2021 in large part due to two factors. These could drive costs down or up depending on how things play out. First, the FDA is much more active against unproven stem cell clinics. This may mean more money from the clinics going toward paying attorneys or FDA compliance experts. Youd think this might drive costs up. However, the still large number of clinics may keep pressure to stay with keeping price tags lower.

The second factor is the COVID-19 pandemic, which has forced many clinics to stop injections temporarily. While a surprising number of clinicsI did by phone were still open in a small informal survey, others were in a holding pattern. This may lower supply which could raise prices. But I think demand is likely way down as many patients stay home to avoid COVID risks. This could be temporary though. As things start re-opening, as they are now, the clinics may be able to capitalize on pent-up demand.

To sum up, the answer to the question, How do stem cells cost? is largely driven by clinic firms aiming to profit. Overall, clinics will charge what they think patients will pay them, which will always be a moving target. I urge patients to be cautious both medically, talking to their doctors, and financially.

Originally posted here:
How much does stem cell therapy cost in 2021? - The Niche

"Stem cell-based therapeutics poised to become mainstream option – BSA bureau

In conversation with Dr Koji Tanabe, Founder and CEO, I Peace, Inc., The United States/Japan

To make the trial investments more meaningful and to avoid ambivalence in animal models, medical science is adopting novel in vitro models of specialised human pluripotent cell lines. Pluripotent stem cells(PSCs) have the agility to expand indefinitely and differentiate into almost any organ-specific cell type. iPSC-derived organs andorganoidsare currently being evaluated in multiple medical research arena like drug development, toxicity testing, drug screening, drug repurposing, regenerative therapies, transgenic studies, disease modeling and more across clinical developments. Innovative pharmacovigilance methodologies are preferring induced pluripotent stem cells (iPSCs) for pre-clinical and clinical investigational studies. Global Induced Pluripotent Stem Cell (iPSC) market is expected to reach $2.3 B by 2026. The iPSC market inAsia-Pacificis estimated to witness fast growth due to increasing R&D projects across countries likeAustralia,JapanandSingapore.

I Peace, Inc. a Palo Alto-based global biotech company with its manufacturing base in Japan, has succeeded in developing and mass-producing clinical grade iPS cells through its proprietary iPS cell manufacturing services. The human iPSC (hiPSC) lines at I Peace leverage differentiated cells across clinical research and medical applications. Biopsectrum Asia discovered more about Japan's stem cell manufacturing ecosystem with Dr Koji Tanabe, Founder and CEO, I Peace, Inc., (The United States/Japan). Tanabe earned his doctorate under Dr Shinya Yamanaka, a Kyoto University researcher who received the 2012 Nobel Prize in Physiology or Medicine for discovery of reprogramming adult somatic cells to pluripotent cells. I Peace is focusing on this Nobel Prize-winning iPSCs technology where Tanabe had played a key role in generating the worlds first successful human iPSCs as one of the team members and is currently industrialising it in the US and Japan.

How do you define Japans Stem cell manufacturing dynamics aligning with regional and APAC market potential?

We believe that human cells play a pivotal role in next-generation drug therapy. Clinical trials of iPSC applications are in full swing not only in Japan, but worldwide as well. In the US, the momentum of clinical trial research is astounding. Yet, mass production of GMP compliant cell products remains a challenge. Entry into this venture is no easy task. As a contract development and manufacturing organisation (CDMO), I Peace is geared to tackle that challenge and become the pioneer of mass production technology of clinical grade cell products.

Can you elaborate I Peaces cost-effective proprietary stem cell synthesis solution and its manufacturing scale?

The key advantage of iPSCs is the ability to create pluripotent cells from an individuals own cells. Furthermore, iPSCs can multiply indefinitely and evolve into any type of cell, making iPSCs an ideal tool for transplant and regenerative medicine and drug research. However, clinical applications of iPSCs to date, utilise heterogenic transplantation. It is because manufacturing of just one line of iPSCs requires a cost intensive clean room to be occupied for several months. Manufacturing process complexities also pose a barrier to cost reduction and mass production.

In contrast, I Peace has developed a proprietary, fully automated closed system for iPS manufacturing, enabling cost-effective production of multiple lines of iPSCs from multiple donors in a single room. Within a few years, we expect to manufacture several thousand lines of iPSCs simultaneously in a single room. With this technology, I Peace can efficiently generate an ample supply of various iPSCs for heterogenic transplant, while also fostering a society where everyone can bank their own iPSCs for potential medical use.

How does I-Peace better position its businesses objectives and go-to-market strategies?

I Peaces manufacturing facility and its processes have undergone rigorous audits and are certified to be in compliance with GMP guidelines of the US, Japan, and Europe. We have the capacity to manufacture clinical-grade iPSCs and iPSC-derived cells for clinical use in the global market. Our manufacturing staff have unparalleled expertise in the manufacturing of iPSCs, and their knowledge and experience make it possible to mass produce high quality clinical-grade iPSCs in the shortest possible time. Additionally, we streamlined the iPSC use licensing scheme to expedite collaborative ventures with downstream partners. We believe these strategies position I Peace as a global leader in iPSC technology.

How do you outline the concept of democratising access to iPSC manufacturing?

At I Peace, we envision a world in which everyone would possess their own iPSCs and if needed, receive autologous transplant medication using their own iPSC. We believe in the importance of raising awareness of Nobel Prize winning iPSC technology and we think much more needs to be done. We need to enlighten the public about iPSCs - what they are, how they are created, and how they play a role in next-generation medical therapies. We also need to underscore the benefits of early banking ones own iPSCs, such as autologous transplant and the fact that cells taken in the early stages of life are preferable over cells collected later in life.

To democratise iPSC access, it is also important to expedite application research. We work closely with downstream partners, and support their iPSC-derived drug therapy development efforts by providing iPSCs to meet their needs. We also collaborate with downstream partners in the development of promising therapies including the use of T-cells for cancer therapy, cardiomyocytes for the treatment of heart disease, and neurocytes for neurological disease.

What is your outlook around boosting public-private stakeholders initiatives to encourage awareness on stem-cell-based therapeutics?

iPSC research has advanced tremendously over the past 16 years, and even more so since Dr Shinya Yamanakas Nobel Prize award in 2012. The acceleration of applied research is paving the way for stem cell-based therapeutics to become a common treatment modality in the near future. As human cell manufacturing requires specialised professional skills and knowledge, it is important to promote functional specialisation. These specialisations include donor recruiting, cell manufacturing (where I Peace is the key player), and implementing cell transplant as a medical practice. We believe that creating a systematic industry structure will build awareness and further drive the growth of stem cell-based therapy.

Can you brief Japans licensing key notes to manufacture and process clinical-grade cells in the region?

Japan enacted three laws to promote the use of regenerative medicine as a national policy:

1) The Regenerative Medicine Promotion Act -- representing the country's determination to promote regenerative medicine;

2) The Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act); and

3) The Act on the Safety of Regenerative Medicine (RM Act). The U.S. also has various tracks such as the Regenerative Medicine Advanced Therapy (RMAT) Designation, Breakthrough Therapy designation, and Fast Track designation.

Of significance, the PMD Act enables a fast-track for regulatory approval of regenerative medicalproducts in Japan. In compliance with the RM Act, I Peace was audited by the PMDA and licensed by the Ministry of Health, Labour, and Welfare to manufacture specific cell products.

Because cell product manufacturing regulations are not standardised globally, cell therapy developers are forced to source GMP iPSCs for each market. I Peace however, has overcome this hurdle. We have built in compliance with global GMP regulations, including FDA's cGMP regulations per 21 CFR 210/211 in our operation. As a result, we can provide cells for global use in multiple markets, accelerating both product development and regulatory approval.

Hithaishi C Bhaskar

hithaishi.cb@mmactiv.com

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"Stem cell-based therapeutics poised to become mainstream option - BSA bureau

Insights on the Stem Cell Banking Global Market to 2026 – by Product Type, Service Type, Bank Type, Utilization, Application and Region – WFMZ…

DUBLIN, July 15, 2021 /PRNewswire/ -- The "Stem Cell Banking Market: Global Industry Trends, Share, Size, Growth, Opportunity and Forecast 2021-2026" report has been added to ResearchAndMarkets.com's offering.

The global stem cell banking market exhibited strong growth during 2015-2020. Stem cell banking is one of the most promising as well as the fastest growing segment of the next-generation stem cell therapy. It is the process of extracting, freezing and storing stem cells for potential future use. Some of the sources through which stem cells are obtained include embryo, umbilical cord, cord blood, placenta and bone marrow. These cells are used for treating a number of different diseases including diabetes, thalassemia, leukemia, sickle cell anemia and cardiac diseases. Moreover, they are also employed for generating platelets, red blood cells and white blood cells. The potential of stem cells to regenerate has led to their applications in tissue engineering, gene therapy and regenerative medicines. Looking forward, the publisher expects the global stem cell banking market to reach a value of US$ 21.5 Billion by 2026.

Global Stem Cell Banking Market Drivers:

Competitive Landscape:

The market is fragmented in nature with the presence various international as well as regional players.

Some of the leading players operating in the market are:

Key Topics Covered:

1 Preface

2 Scope and Methodology

3 Executive Summary

4 Introduction

4.1 Overview

4.2 Properties

4.3 Key Industry Trends

5 Global Stem Cell Banking Market

5.1 Market Overview

5.2 Market Performance

5.3 Impact of COVID-19

5.4 Market Breakup by Product Type

5.5 Market Breakup by Service Type

5.6 Market Breakup by Bank Type

5.7 Market Breakup by Utilization

5.8 Market Breakup by Application

5.9 Market Breakup by Region

5.10 Market Forecast

6 Market Breakup by Product Type

6.1 Adult Stem Cells

6.1.1 Market Trends

6.1.2 Market Forecast

6.2 Human Embryonic Cells

6.2.1 Market Trends

6.2.2 Market Forecast

6.3 IPS Cells

6.3.1 Market Trends

6.3.2 Market Forecast

7 Market Breakup by Service Type

7.1 Sample Preservation and Storage

7.1.1 Market Trends

7.1.2 Market Forecast

7.2 Sample Analysis

7.2.1 Market Trends

7.2.2 Market Forecast

7.3 Sample Processing

7.3.1 Market Trends

7.3.2 Market Forecast

7.4 Sample Collection and Transportation

7.4.1 Market Trends

7.4.2 Market Forecast

8 Market Breakup by Bank Type

8.1 Private

8.1.1 Market Trends

8.1.2 Market Forecast

8.2 Public

8.2.1 Market Trends

8.2.2 Market Forecast

9 Market Breakup by Utilization

9.1 Used

9.1.1 Market Trends

9.1.2 Market Forecast

9.2 Unused

9.2.1 Market Trends

9.2.2 Market Forecast

10 Market Breakup by Application

10.1 Personalized Banking Applications

10.1.1 Market Trends

10.1.2 Market Forecast

10.2 Research Applications

10.2.1 Market Trends

10.2.2 Market Forecast

10.3 Clinical Applications

10.3.1 Market Trends

10.3.2 Market Forecast

11 Market Breakup by Region

11.1 North America

11.1.1 Market Trends

11.1.2 Market Forecast

11.2 Europe

11.2.1 Market Trends

11.2.2 Market Forecast

11.3 Asia Pacific

11.3.1 Market Trends

11.3.2 Market Forecast

11.4 Middle East and Africa

11.4.1 Market Trends

11.4.2 Market Forecast

11.5 Latin America

11.5.1 Market Trends

11.5.2 Market Forecast

12 Global Stem Cell Banking Industry: SWOT Analysis

12.1 Overview

12.2 Strengths

12.3 Weaknesses

12.4 Opportunities

12.5 Threats

13 Global Stem Cell Banking Industry: Value Chain Analysis

14 Global Stem Cell Banking Industry: Porters Five Forces Analysis

14.1 Overview

14.2 Bargaining Power of Buyers

14.3 Bargaining Power of Suppliers

14.4 Degree of Competition

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Insights on the Stem Cell Banking Global Market to 2026 - by Product Type, Service Type, Bank Type, Utilization, Application and Region - WFMZ...

Base Editing as Therapy for Common Inherited Lung and Liver Disease Shows Promise – Clinical OMICs News

Scientists say that base editing proved itself efficient in correcting a mutation in patient cells with the monogenic disease Alpha-1 antitrypsin deficiency (AATD). The disorder is a common inherited disease that affects the liver and the lungs.

Base editing is different from other forms of editing, including CRISPR, because the base editors do not induce a break in the DNA, which helps prevent double strand breaks, potential off-target editing, and unwanted mutations during cell repair.

Researchers at Boston Medical Center and Boston University used patient-derived liver cells (iHeps) that mimic the biology of liver hepatocytes, the main producers of alpha-1 antitrypsin protein in the body. The base editing technology corrected the Z mutation responsible for AATD and reduced the effects of the disease in the hepatocytes, demonstrating successful base editing in human cells.

The study (Adenine Base Editing Reduces Misfolded Protein Accumulation and Toxicity in Alpha-1 Antitrypsin Deficient Patient iPSC-Hepatocytes), published inMolecular Therapy,can help pave the way for future human trials, according to the research team.

AATD is most commonly caused by the Z mutation, a single base substitution that leads to AAT protein misfolding and associated liver and lung disease. In this study, we apply adenine base editors to correct the Z mutation in patient-induced pluripotent stem cells (iPSCs) and iPSC-derived hepatocytes (iHeps), wrote the investigators.

We demonstrate that correction of the Z mutation in patient iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base editing (ABE) of differentiated iHeps decreases ER stress in edited cells as demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in iPSCs and do not identify off-target genomic mutations by whole genome sequencing.

These results reveal the feasibility and utility of base-editing to correct the Z mutation in AATD patient cells.

This study shows the successful application of base editing technology to correct the mutation responsible for AATD in liver cells derived from patients with this disease, said Andrew Wilson, MD, a pulmonologist at Boston Medical Center and an associate professor of medicine at the Boston University School of Medicine, who served as the studys corresponding author. I am hopeful that these results will create a pathway to use this technology to help patients with AATD and other monogenic diseases.

Base editors created by Beam Therapeutics were applied to induced pluripotent stem cells (iPS cells) from patients with AATD, and then again in hepatocytes that were derived from iPS cells. This was done to study the correction of the Z mutation of the gene responsible for AATD in human cells.

The Z mutation in the SERPINA1 gene is responsible for causing chronic, progressive lung and liver disease in AATD. In patients with AATD, the mutant AAT proteins misfold and form aggregates of protein that build up inside the hepatocytes and cause damage.

For this study, researchers started with mutant (ZZ) iPSCs created from a patient with AATD. After the base editing process was completed, the DNA from the edited cells was sequenced to determine if the SERPINA1 gene had been corrected. Clonal populations of cells with either one (MZ) or both copies (MM) of the corrected gene were expanded and then differentiated over the course of 25 days to generate hepatocytes.

After sequencing the entire genome of the edited cells, there was no evidence of inadvertent mutations in the genome from the base editors, and the misfolding and associated protein buildup was partially corrected in MZ cells and completely in MM normal cells.

The process was repeated using hepatocytes derived from the mutant iPSCs. Two base editors were used in different conditions to test the efficiency of this process. In the best conditions, about 50% of the mutant genes were successfully edited. The cells were then analyzed to see if they still appeared hepatic and if there were fewer signs of the disease in the edited cells, compared to mutant ZZ cells.

Findings showed the base editing did not alter the hepatic program, and the liver cells still expressed hepatic genes and proteins at normal levels. In addition, there was less accumulation of aggregated misfolded Z AAT protein, showing less evidence of disease in the edited cells.

While augmentation therapy has been shown to slow the progression of lung disease in AATD patients, there are currently no treatments available for AATD-associated liver disease. Emerging treatment strategies have focused on the correction of the Z mutation.

Base editing is being evaluated as a treatment modality for a variety of monogenic diseases, according to the scientists. Alpha-1 antitrypsin deficiency is a prime target for base editing, likely to be one of the earlier diseases in which base editors are tried in human studies. Additional disease targets include retinal disease, hereditary tyrosinemia, sickle cell anemia, progeria, cystic fibrosis, and others.

Findings of this study suggest that future research may explore the usefulness of base-editors in editing other quiescent cell populations. Additionally, it has recently been shown that base-editors can edit RNA in addition to DNA in immortalized cell lines and warrants further investigation.

By quiescent, we are referring to differentiated cells (in this case hepatocytes) that are not stem cells or cells that are actively dividing. Basically, [we are talking about] any differentiated cell type, Wilson toldGEN. This is relevant because many of the cell types in the body that you would want to target are already differentiated cells. It is in many cases easier to edit an actively dividing cell, which is why we mention this. There are many examples of a differentiated cell type in the body, such as cardiac cells, lung cells, skin cells, etc., that you might want to target.

One of the major things researchers worry about in the field of gene editing is the possibility of off-target effectsunintended consequences of applying the editing machinery.

The most likely off-target effect, in this case, would be editing of DNA somewhere in the genome other than what we intended to edit, continued Wilson. When we looked by whole genome sequencing, we didnt see evidence of this in iPS cells. However, in addition to editing DNA, it has been reported that base editors can also edit RNA. This could have unintended consequences even if the DNA sequence isnt changed.

We didnt look in this study to see if this occurred, which is why we mentioned itjust to be up front about possible unintended consequences/toxicities that could be present and that we didnt exclude. It isnt something specific to our study or gene of interest but generalizable to the entire field of base editing.

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Base Editing as Therapy for Common Inherited Lung and Liver Disease Shows Promise - Clinical OMICs News

The Possibility Of New CAR-T Cell Therapy For Multiple Myeloma – Powdersvillepost.com

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Multiple myeloma scientists at the Mayo Clinic are investigating a possible innovative chimeric antigen receptor-T cell treatment (CAR-T cell treatment) called antigen receptor therapy. Their results have been authored in the Lancet on June 24.

According to Yi Lin, M.D., a refer researcher at the Mayo Clinic, CAR-T cell treatment is a form of immunotherapeutic that harnesses the authority of an individuals own immune response by designing their T cells to recognise and kill the cancer cell.

Idecabtagenevicleucel, the first CAR-T cell therapy for numerous myeloma was first authorised by the Food and Drug Administration in March, according to Dr. Lin. In our ongoing work on a prospective CAR cell diagnosis for numerous myeloma Dr. Lin notes, Presently, we are going to work forward into some other prospective CAR cell therapy for numerous myeloma.

Dr. Lin says that CARTITUDE-1 research is a phase 1B/II clinical trial, the first of three enrollment trials. CAR-T cell treatment was evaluated in numerous myeloma patient populations who had done receive three or more lines of conventional drug treatment and who were still on proteasome inhibitors, immunostimulatory medications, and CD38 antibodies.

Cilta-cel is a singular injection created from the sufferers original T cells that were biologically modified explains Dr. Lin. According to Dr. Lin, the treatments total reaction percentage is 97 percent, with full remission & advancement life percentages of 67 percent & 77 percent, correspondingly. Ultimately, 89 percent of the people survived.

Notifications on the research are just given at American Society of Medical Oncology yearly conference, said Dr. Lin, this happened before our article is published in The Lancet. This ASCO report demonstrated that individuals getting this treatment had a continuing deeper responder, via an 80 percent full reaction frequency adds Dr. Lin. Those are outstanding findings in myeloma individuals who had previously had multiple rounds of treatment.

Dr. Lin believes that it would be critical in the future to fully comprehend the medical characteristics of individuals who have had sustained remissions on this medication, as well as the processes that cause individuals to revert.

Although official contrasts between 2 distinct study designs of ide-cel&cilta-cel cannot be made, Dr. Lin adds, the extremely overall responder rates and advancement patient survival administered with cilta-cel were extremely promising.

She warns, though, that turning this study into a therapeutic customised medicine would necessitate addressing a slew of technical problems particularly assuring that the transfer from study to retail venture is seamless.

The exorbitant expense of CAR T cell treatment is a major concern. The fact that CAR T cells must be custom-made for each patient is one of the key explanations for the increased cost. To overcome this problem, many scientists are currently attempting to generate off the shelf CAR T cells that are derived from donors and may be utilised to treat a wide range of sufferers. CAR T cells produced from allogeneic donors are one option.

Genome editing techniques can be used to remove the T cell receptors that may produce an allogeneic immune response. CAR T cells generated from iPS cells are another potential technique. Some studies have extensively successful in creating functioning T cells from iPS cells, which they are now attempting to employ as a source for CAR T cells.

Excerpt from:
The Possibility Of New CAR-T Cell Therapy For Multiple Myeloma - Powdersvillepost.com

MoHAP, EHS reveal immunotherapy for cancer, viral infections at Arab Health 2021 – WAM EN

ABU DHABI, 22nd June, 2021 (WAM) -- The Ministry of Health and Prevention (MoHAP) and the Emirates Health Services (EHS) recently revealed innovative immunotherapy for cancer and viral infections in cooperation with Japans Kyoto University.

This came during the participation of the ministry and the EHS at the Arab Health 2021 which began in Dubai on 21st June and concludes on 24th June.

The treatment is based on the clinical application of the therapy using T cell preparation after it was discovered that such cells can fight cancer and viral infections. The T cell medicine will be produced using the iPS cell technology.

T Cell makes up a group of lymphocytes present in the blood and plays a major role in cellular immunity. It is possible to produce T cells in large numbers and store them in appropriate conditions to be administered to patients when needed.

Thus, by the success of this project, patients with cancer or viral infection may have great merit in which they can make very easy access to T cell therapy.

Strategic partnerships Dr. Youssef Mohamed Al Serkal, Director-General of the Emirates Health Services, spoke about the commitment of the ministry and the EHS to having strategic partnerships with the most prestigious medical research centres while keeping an eye on the sustainable investment in future healthcare services.

"Although the prevalence of cancer in the UAE is considered lower than in other parts of the world, we work hard to make a qualitative shift in cancer and viral infection healthcare," Al Serkal stated, adding, "This is part of our strategy to provide healthcare services in innovative and sustainable ways and implement the national strategy to reduce cancer mortality rates."

Al Serkal pointed out that the ministry and EHS support the National Cancer Control Programme and prepare a road map to achieve the target indicator. They also analyse the current status of cancer diseases and their diagnostic and therapeutic pathways, support research and studies on the control of cancer diseases and viral infections, and back workshops and educational and training activities. awareness campaigns, and innovative initiatives.

Dr. Kalthum Al Balushi, Director of Hospitals Department, said, "The ground-breaking treatment technology for cancer and viral infections, in cooperation with the Kyoto University, represents a paradigm shift in health services provided by the Ministry and the EHS."

The treatment is based on stimulating immune cells to fight cancer cells using pluripotent stem cells, which is a recent global trend that has begun to open great prospects for improving the quality of life of patients, Al Balushi added.

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MoHAP, EHS reveal immunotherapy for cancer, viral infections at Arab Health 2021 - WAM EN

Global Induced Pluripotent Stem Cells Market Analysis By Future Demand, Top Players, Industry Share Size, Revenue and Growth Rate Through…

Databridgemarketresearch.com Present Global Induced Pluripotent Stem Cells Market Industry Trends and Forecast to 2027 new report to its research database. The report spread No of pages : 350 No of Figures: 60 No of Tables: 220 in it.

Induced pluripotent stem cells (iPSCs) marketis expected to gain market growth in the forecast period of 2020 to 2027. Data Bridge Market Research analyses the market to account to USD 2,442.97 million by 2027 growing at a CAGR of 7.5% in the above-mentioned forecast period. Increasing R&D investment activities is expected to create new opportunity for the market.

Induced pluripotent stem cells market report helps businesses to look for a better solution to refine their business strategies with which they can succeed in this competitive market place. This report underlines the moves of key market players like product launches, joint ventures, developments, mergers and acquisitions which is affecting the market and healthcare Industry as a whole and also affecting the sales, import, export, revenue and CAGR values. All the statistical and numerical data that has been forecasted in the winning Induced pluripotent stem cells report is represented with the help of graphs, charts, or tables which makes this report more user friendly.

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Few of the major competitors currently working in global induced pluripotent stem cells market areFUJIFILM Holdings Corporation, Astellas Pharma Inc, Fate Therapeutics, Bristol-Myers Squibb Company, ViaCyte, Inc., CELGENE CORPORATION, Vericel Corporation, KCI Licensing, Inc, STEMCELL Technologies Inc., Japan Tissue Engineering Co., Ltd., Organogenesis Holdings Inc, Lonza, Takara Bio Inc., Horizon Discovery Group plc, Thermo Fisher Scientific.

Study Objectives Of Induced pluripotent stem cells Market

Global Induced Pluripotent Stem Cells (iPSCs) Market Scope and Market Size

Induced pluripotent stem cells (iPSCs) market is segmented of the basis of derived cell type, application and end- user. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

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Global Induced Pluripotent Stem Cells Market Drivers:

Increasing R&D investment activities is expected to create new opportunity for the market.

Increasing demand for personalized regenerative cell therapies among medical researchers & healthcare is expected to enhance the market growth. Some of the other factors such as increasing cases of chronic diseases, growing awareness among patient, rising funding by government & private sectors and rising number ofclinical trialsis expected to drive the induced pluripotent stem cells (iPSCs) market in the forecast period of 2020 to 2027.

High cost of the induced pluripotent stem cells (iPSCs) and increasing ethical issues & lengthy processes is expected to hamper the market growth in the mentioned forecast period.

Key Developments in the Market:

TOC of Induced Pluripotent Stem Cells Market Report Contains:

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Upcoming Opportunities in CAR T-cell Therapy Market: Future Trend and Analysis of Key Segments and Forecast 2021 to 2026 NeighborWebSJ -…

Global CAR T-cell Therapy Market 2021-2026 by Type, by Applications, and Region: Trend Outlook and Growth Opportunity is based on comprehensive research of the global CAR T-cell Therapy market with all its key segments through extensively detailed classifications. this report study consists of profound analysis and assessment generated from premium primary and secondary information sources with inputs derived from industry professionals across the value chain.

This report provides a detailed historical analysis of the global market for CAR T-cell Therapy from 2016-2020 and provides extensive market forecasts from 2021-2026 by region or country level. It covers the sales volume, price, revenue, gross margin, historical growth, and future perspectives in the CAR T-cell Therapy market.

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In-depth qualitative analyses include identification and investigation of the following aspects:

Leading Players of CAR T-cell Therapy market including:

CAR T-cell Therapy Market offers industry standpoint with development, Size, Share, Key Players procedures examination and memorable and cutting-edge pattern. This CAR T-cell Therapy Market report concedes the serious and quickly advancing industry, promoting guidance to follow execution and settle on choices such as both continuance and development.

Market split by Type can be divided into:

Market split by Application can be divided into:

CAR T-cell Therapy Market segment by Region/Country including:

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The COVID-19 Pandemic has created bottlenecks across industry pipelines, sales funnels, and supply chain activities. This has created unprecedented budget pressure on company spending for industry leaders. This has increased the requirement for opportunity analysis, price trend knowledge, and competitive outcomes. This CAR T-cell Therapy market report helps its business players to grow in these uncertain markets.

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Upcoming Opportunities in CAR T-cell Therapy Market: Future Trend and Analysis of Key Segments and Forecast 2021 to 2026 NeighborWebSJ -...

Stem Cell Therapy Market to Score Past US$ 40.3 Billion Valuation by 2027: At a CAGR of 21.1% KSU | The Sentinel Newspaper – KSU | The Sentinel…

GlobalStem Cell Therapy Market,by Cell Source (Adult Stem Cells, Induced Pluripotent Stem Cells, Embryonic Stem Cells, and Others), by Application (Musculoskeletal Disorders, Wounds and Injuries, Cancer, Autoimmune Disorders, and Others), and byRegion(North America, Latin America, Europe, Asia Pacific, Middle East, and Africa),was valued atUS$ 7,313.6million in 2018, and is expected to exhibit a CAGR of21.1%over the forecast period (2019-2027),as highlighted in a new report published by .Increasing application of stem cells for the treatment of patients with blood-related cancers, spinal cord injury and other diseases are the leading factors that are expected to drive growth of stem cell therapy market over the forecast period.

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According to the National Spinal Cord Injury Statistical Center, 2016, the annual incidence of spinal cord injury (SCI) is approximately 54 cases per million population in the U.S. or approximately 17,000 new SCI cases each year. Moreover, according to the Leukemia and Lymphoma Society, 2017, around 172,910 people in the U.S. were diagnosed with leukemia, lymphoma or myeloma in 2017, thus leading to increasing adoption of stem cells for its efficient treatment. Increasing product launches by key players such as medium for developing embryonic stem cells is expected to propel the market growth over the forecast period.

For instance, in January 2019, STEMCELL Technologies launched mTeSR Plus, a feeder-free human pluripotent stem cell (hPSC) maintenance medium for avoiding conditions associated with DNA damage, genomic instability, and growth arrest in hPSCs. With the launch of mTeSR, the company has expanded its portfolio of mediums for maintenance of human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells.

Increasing research and development of induced pluripotent stem cells coupled with clinical trials is expected to boost growth of the stem cell therapy market over the forecast period. For instance, in April 2019, Fate Therapeutics in collaboration with UC San Diego researchers launched Off-the-shelf immunotherapy (FT500) developed from human induced pluripotent stem cells. The therapy is currently undergoing clinical trials for the treatment of advanced solid tumors.

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North America is expected to hold a dominant position in the stem cell therapy market over the forecast period, owing increasing number of clinical trials to cater to unmet medical needs of the patients is a major factor driving growth of the stem cell therapy market. For instance, in April, 2019, UCLA-UCI Alpha Stem Cell Clinic participated in a new clinical research study to investigate a stem cell product CTX0E03 DP, in order to improve function in people with chronic disability from ischemic stroke. The study, called PISCES III, is currently in phase IIb clinical study. Moreover, manufacturers are focused on collaborating with academic researchers to help expand the potential use of newborn stem cell therapies that may be available to patients, which is expected to facilitate growth of the market over the forecast period. For instance, in February 2018, the Institute of Integrative Biology entered into a collaboration with Anika Therapeutics, Inc., to develop an injectable mesenchymal stem cell (MSC) therapy for the treatment of osteoarthritis in patients.

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Stem Cell Therapy Market to Score Past US$ 40.3 Billion Valuation by 2027: At a CAGR of 21.1% KSU | The Sentinel Newspaper - KSU | The Sentinel...

Research and therapy with induced pluripotent stem cells …

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Research and therapy with induced pluripotent stem cells ...

Global Induced Pluripotent Stem Cells (iPSCs) Market Expectable to Exceed Global Market Revenue, Size, Segments and Market Competition Trend to…

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Some of the key players profiled in the report areFUJIFILM Holdings Corporation, Astellas Pharma Inc, Fate Therapeutics, Bristol-Myers Squibb Company, ViaCyte, Inc., CELGENE CORPORATION, Vericel Corporation, KCI Licensing, Inc, STEMCELL Technologies Inc., Japan Tissue Engineering Co., Ltd., Organogenesis Holdings Inc, Lonza, Takara Bio Inc., Horizon Discovery Group plc, Thermo Fisher Scientific.

Global Induced Pluripotent Stem Cells (iPSCs) Market Scope and Market Size

Induced pluripotent stem cells (iPSCs) market is segmented of the basis of derived cell type, application and end- user. The growth amongst these segments will help you analyse meagre growth segments in the industries, and provide the users with valuable market overview and market insights to help them in making strategic decisions for identification of core market applications.

Key Developments in the Market:

In March 2018, Kaneka Corporation announced that they have acquired a patent in the Japan for the creation of the method to mass-culture pluripotent stem cells including iPS cells and ES cells. This will help the company to use the technology to produce high quality pluripotent stem cells which can be used in the drug and cell therapy.

In March 2015, Fujifilm announced that they have acquired Cellular Dynamics International. The main aim of the acquisition is to expand their business in the iPS cell-based drug discovery support service with the use of CDS technology. It will help them to product high- quality automatic human cells with the help of the induced pluripotent stem cells. This will help the company to be more competitive in the drug discovery and regenerative medicine.

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Global Induced Pluripotent Stem Cells (iPSCs) Market Drivers:

Increasing R&D investment activities is expected to create new opportunity for the market.

Increasing demand for personalized regenerative cell therapies among medical researchers & healthcare is expected to enhance the market growth. Some of the other factors such as increasing cases of chronic diseases, growing awareness among patient, rising funding by government & private sectors and rising number ofclinical trialsis expected to drive the induced pluripotent stem cells (iPSCs) market in the forecast period of 2020 to 2027.

High cost of the induced pluripotent stem cells (iPSCs) and increasing ethical issues & lengthy processes is expected to hamper the market growth in the mentioned forecast period.

Table of Contents:

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Global Induced Pluripotent Stem Cells (iPSCs) Market Expectable to Exceed Global Market Revenue, Size, Segments and Market Competition Trend to...

Evotec and Sartorius Partner with Start-Up Curexsys on IPSC-Based Therapeutic Exosome Approach – BioSpace

HAMBURG, GERMANY / ACCESSWIRE / December 9, 2020 / Evotec SE (Frankfurt Stock Exchange: EVT, MDAX/TecDAX, ISIN: DE0005664809) and the life science company Sartorius announced today that they have entered into a partnership with the recently established Curexsys GmbH, a Goettingen, Germany-based technology leader specialising in the emerging field of therapeutic exosomes.

Curexsys delivers a proprietary isolation technology for exosomes based on a traceless immune-affinity process. This process is different from commonly used antibody-based processes and enables the company to overcome a key hurdle in exosome preparation, i.e. remaining antibodies in the final preparation. Curexsys is founded by Herbert Stadler, a serial biotech entrepreneur, and Jens Gruber, a former group leader of Medical RNA Biology who is going to lead Curexsys as Chief Scientific Officer.

Under the terms of the agreement, Evotec and Curexsys will collaborate with the production of Human Mesenchymal Stem Cells ("MSCs"), which serve as a source for exosomes. These are small vesicles that are naturally released from a cell. They contain proteins, nucleic acids and metabolites, which carry information from secreting to receiving cells. Exosomes have immunomodulatory and anti-inflammatory effects, which makes them a promising novel approach for innovative regenerative therapies, as therapeutics in age-related conditions, but also for diagnostic purposes. Curexsys aims to develop targeted approaches for a variety of diseases, initially focusing on Sicca Syndrome, commonly known as "dry eye", an inflammatory condition affecting 14% to 17% of the adult population for whom there is currently no effective treatment available.

The collaboration combines Evotec's industry-leading induced Pluripotent Stem Cell ("iPSC") platform with Curexsys' proprietary technology to selectively isolate exosomes. Sartorius will support Curexsys to set up a GMP-compliant and scalable manufacturing platform.

Furthermore, Evotec and Sartorius have formed a consortium to jointly invest in Curexsys' 8.2 m seed financing round with Evotec acquiring an equity stake of approx. 37% in Curexsys and Sartorius of approx. 21%.

Dr Cord Dohrmann, Chief Scientific Officer of Evotec, commented: "Therapeutic exosomes hold significant promise for regenerative medicine and beyond. Steadily increasing evidence suggests that exosomes derived from stem cells can aid tissue repair and engineering vesicles could carry drugs to diseased tissues. These efforts have been held back by a dearth of standardised methods to isolate and study vesicles. Combining Evotec's industrial-grade iPSC and PanOmics platforms with Curexsys' proprietary exosome isolation technology and Sartorius' ability to translate these into a fully GMP-compliant process is a unique opportunity to build the leading exosome company in the industry."

Dr Ren Faber, Head of Sartorius' Bioprocess Solutions Division, said: "With our integrated portfolio of manufacturing solutions Sartorius is the 'go-to' partner for developers of such new modalities when it comes to implementing GMP-compliant, flexible production processes. We are very much looking forward to contributing our proven and scalable technology platform to Curexsys process and help them achieve their next milestones faster."

Dr Jens Gruber, Chief Scientific Officer of Curexsys, added: "We are very happy that we were able to form such a consortium with industry leaders in their field. This unique constellation gives Curexsys an optimal starting position to advance our technologies for highly specific isolation of exosomes and to rapidly approach therapeutic applications."

About Exosomes and CurexsysExosomes are extracellular, nanoscale vesicles that are actively secreted from cells to transfer information to neighbouring cells and distant tissues. Exosomes carry information of secreting to receiving cells utilising proteins, nucleic acids and metabolites. MSC-derived exosomes function as paracrine mediators that limit inflammation, reprogram immune cells, and activate endogenous repair pathways, recapitulating to a large extent the therapeutic effects of parental MSCs. Exosomes hold potential as diagnostics, as therapeutics and cosmeceuticals. More than 100 clinical trials involving exosomes are currently ongoing, demonstrating their broad therapeutic potential.

Curexsys is a Goettingen, Germany-based start-up company founded by molecular biologist Dr Jens Gruber and the biochemist and serial entrepreneur Dr Herbert Stadler. With a scalable and semi-automated proprietary system for traceless immune-affinity cell sorting, Curexsys aims to become the leading supplier for clinical grade exosomes in regenerative medicine and anti-aging therapies.

About Evotec and iPSCInduced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

Evotec has built an industrialised iPSC infrastructure that represents one of the largest and most sophisticated iPSC platforms in the industry. Evotec's iPSC platform has been developed over the last years with the goal to industrialise iPSC-based drug screening in terms of throughput, reproducibility and robustness to reach the highest industrial standards, and to use iPSC-based cells in cell therapy approaches via the Company's proprietary EVOcells platform.

ABOUT SARTORIUSThe Sartorius Group is a leading international partner of life science research and the biopharmaceutical industry. With innovative laboratory instruments and consumables, the Group's Lab Products & Services Division concentrates on serving the needs of laboratories performing research and quality control at pharma and biopharma companies and those of academic research institutes. The Bioprocess Solutions Division with its broad product portfolio focusing on single-use solutions helps customers to manufacture biotech medications and vaccines safely and efficiently. The Group has been annually growing by double digits on average and has been regularly expanding its portfolio by acquisitions of complementary technologies. In fiscal 2019, the company earned sales revenue of some 1.83 billion euros. At the end of 2019, more than 9,000 people were employed at the Group's approximately 60 manufacturing and sales sites, serving customers around the globe.

SARTORIUS CONTACTPetra KirchhoffHead of Corporate Communications and Investor Relations+49 (0)551.308.3684 petra.kirchhoff@sartorius.comwww.sartorius.com

ABOUT EVOTEC SEEvotec is a drug discovery alliance and development partnership company focused on rapidly progressing innovative product approaches with leading pharmaceutical and biotechnology companies, academics, patient advocacy groups and venture capitalists. We operate worldwide and our more than 3,400 employees provide the highest quality stand-alone and integrated drug discovery and development solutions. We cover all activities from target-to-clinic to meet the industry's need for innovation and efficiency in drug discovery and development (EVT Execute). The Company has established a unique position by assembling top-class scientific experts and integrating state-of-the-art technologies as well as substantial experience and expertise in key therapeutic areas including neuronal diseases, diabetes and complications of diabetes, pain and inflammation, oncology, infectious diseases, respiratory diseases, fibrosis, rare diseases and women's health. On this basis, Evotec has built a broad and deep pipeline of more than 100 co-owned product opportunities at clinical, pre-clinical and discovery stages (EVT Innovate). Evotec has established multiple long-term alliances with partners including Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CHDI, Novartis, Novo Nordisk, Pfizer, Sanofi, Takeda, UCB and others. For additional information please go to http://www.evotec.com and follow us on Twitter @Evotec.

FORWARD LOOKING STATEMENTSInformation set forth in this press release contains forward-looking statements, which involve a number of risks and uncertainties. The forward-looking statements contained herein represent the judgement of Evotec as of the date of this press release. Such forward-looking statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.

SOURCE: Evotec AG via EQS Newswire

View source version on accesswire.com:https://www.accesswire.com/620112/Evotec-and-Sartorius-Partner-with-Start-Up-Curexsys-on-IPSC-Based-Therapeutic-Exosome-Approach

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Evotec and Sartorius Partner with Start-Up Curexsys on IPSC-Based Therapeutic Exosome Approach - BioSpace

A Potential Therapy for One of the Leading Causes of Heart Disease – PRNewswire

After 15 years of unrelenting work, a team of scientists from Gladstone Institutes has now discovered a potential drug candidate for heart valve disease that works in both human cells and animals and is ready to move toward a clinical trial. Their findings were just published in the journal Science.

"The disease is often diagnosed at an early stage and calcification of the heart valves worsens over the patient's lifetime as they age," says Gladstone President and Director of the Roddenberry Stem Cell Center Deepak Srivastava, MD,who led the study. "If we could intervene early in life with an effective drug, we could potentially prevent the disease from occurring. By simply slowing the progression and shifting the age of people who require interventions by 5 or 10 years, we could avoid tens of thousands of surgical valve replacements every year."

This also applies to the millions of Americansabout one to two percent of the populationwith a congenital anomaly called bicuspid aortic valve, in which the aortic valve only has two leaflets instead of the normal three. While some people may not even know they have this common heart anomaly, many will be diagnosed as early as their forties.

"We can detect this valve anomaly through an ultrasound," explains Srivastava, who is also a pediatric cardiologist and a professor in the Department of Pediatrics at UC San Francisco (UCSF). "About a third of patients with bicuspid aortic valve, which is a very large number, will develop enough calcification to require an intervention."

Srivastava's research into heart valve disease started in 2005, when he treated a family in Texas who had this type of early-onset calcification. All these years later, thanks to the family's donated cells, his team has finally found a solution to help them and so many others.

A Holistic Approach in the Hunt for a Therapy

Members of the family treated by Srivastava had disease that crossed five generations, enabling the team to identify the causea mutation in one copy of the gene NOTCH1. Mutations in this gene cause calcific aortic valve disease in approximately four percent of patients and can also cause thickening of valves that trigger problems in newborns. In the other 96 percent of cases, the disease occurs sporadically.

"The NOTCH1 mutation provided a foothold for us to figure out what goes wrong in this common disease, but most people won't have that mutation," says Srivastava. "However, we found that the process that leads to the calcification of the valve is mostly the same whether individuals have the mutation or not. The valve cells get confused and start thinking they're bone cells, so they start laying down calcium and that leads to hardening and narrowing of the valves."

In the hunt for a treatment, the group of scientists chose a novel, holistic approach rather than simply focusing on a single target, such as the NOTCH1 gene.

"Our goal was to develop a new framework to discover therapeutics for human disease," says Christina V. Theodoris, MD, PhD, lead author of the study who is now completing her residency in pediatric genetics at Boston Children's Hospital. "We wanted to find promising therapies that could treat the disease at its core, as opposed to just treating some specific symptoms or peripheral aspects of the disease."

When Theodoris first joined Srivastava's lab at Gladstone, she was a graduate student at UCSF. At the time, they knew the NOTCH1 gene mutation caused valve disease, but they didn't have the tools to study the problem further, largely because it was very difficult to obtain valve cells from patients.

"My first project was to convert the cells from the patient families into induced pluripotent stem (iPS) cells, which have the potential of becoming any cell in the body, and turn them into cells that line the valve, allowing us to understand why the disease occurs," says Theodoris. "My second project was to make a mouse model of calcific aortic valve disease. Only then could we start using these models to identify a therapy."

One Drug Candidate Rises to the Top

For this latest study, the scientists searched for drug-like molecules that could correct the overall network that goes awry in heart valve disease and leads to calcification. To do so, they first had to determine the network of genes that are turned on or off in diseased cells.

Then, they used an artificial intelligence method, training a machine learning program to detect whether a cell was healthy or sick based on this network of genes. They subsequently treated diseased human cells with nearly 1,600 molecules to see if any drugs shifted the network in the cells enough that the machine learning program would reclassify them as healthy. The researchers identified a few molecules that could correct diseased cells back to the normal state.

"Our first screen was done with cells that have the NOTCH1 mutation, but we didn't know if the drugs would work on the other 96 percent of patients with the disease," says Srivastava.

Fortunately, Anna Malashicheva, PhD, from the Russian Academy of Sciences, had collected valve cells from over 20 patients at the time of surgical replacement, and Srivastava struck up a fruitful collaboration with her group to do a "clinical trial in a dish."

"We tested the promising molecules on cells from these 20 patients with aortic valve calcification without known genetic causes," Srivastava adds. "Remarkably, the molecule that seemed most effective in the initial study was able to restore the network in these patients' cells as well."

Once they had identified a promising candidate in cells in a dish for both NOTCH1 and sporadic cases of calcific aortic valve disease, Srivastava and his team did a "pre-clinical trial" in a mouse model of the disease. They wanted to determine whether the drug-like molecule would actually work in a whole, living organ.

The scientists confirmed that the therapeutic candidate could successfully prevent and treat aortic valve disease. In young mice who had not yet developed the disease, the therapy prevented the calcification of the valve. And in mice that already had the disease, the therapy actually halted the disease and, in some cases, led to reversal of the disease. This finding is especially important since most patients aren't diagnosed until calcification has already begun.

"Our strategy to identify gene networkcorrecting therapies that treat the core disease mechanism may represent a compelling path for drug discovery in a range of other human diseases," says Theodoris. "Many therapeutics found in the lab don't translate well to humans or focus only on a specific symptom. We hope our approach can offer a new direction that could increase the likelihood of candidate therapies being effective in patients."

The researchers' strategy relied heavily on technological advancements, including human iPS cells, gene editing, targeted RNA sequencing, network analysis, and machine learning.

"Our study is a really good example of how modern technologies are facilitating the kinds of discoveries that are possible today, but weren't not so long ago," says Srivastava. "Using human iPS cells and gene editing allowed us to create a large number of cells that are relevant to the disease process, while powerful machine learning algorithms helped us identify, in a non-biased fashion, the important genes for distinguishing between healthy and diseased cells."

"By using all the knowledge we gathered over a decade and a half, combined with the latest tools, we were able to find a drug candidate that can be taken to clinical trials," he adds. "Our ultimate goal is always to help patients, so the whole team is very pleased that we found a therapy that could truly improve lives."

About the Research Project

The paper, "Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease,"was published online by Science on December 10, 2020.

Other authors include Ping Zhou, Lei Liu, Yu Zhang, Tomohiro Nishino, Yu Huang, Sanjeev S. Ranade, Casey A. Gifford, Sheng Ding from Gladstone; Aleksandra Kostina from the Russian Academy of Sciences; and Vladimir Uspensky from the Almazov Federal Medical Research Centre in Russia.

The work was funded by the California Institute of Regenerative Medicine; the National Heart, Lung, and Blood Institute; and the National Center for Research Resources. Gladstone researchers also received support from the Winslow Family, the L.K. Whittier Foundation, The Roddenberry Foundation, the Younger Family Fund, the American Heart Association, several programs and fellowships at UCSF, residency programs from Boston Children's Hospital and the Harvard Medical School, the Uehara Memorial Foundation, and a Howard Hughes Medical Institute Fellowship of the Damon Runyon Cancer Research Foundation.

About Gladstone Institutes

To ensure our work does the greatest good, Gladstone Institutes focuses on conditions with profound medical, economic, and social impactunsolved diseases. Gladstone is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease.

Media Contact: Julie Langelier | Assistant Director, Communications | [emailprotected] | 415.734.5000

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A Potential Therapy for One of the Leading Causes of Heart Disease - PRNewswire

Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo – Science Advances

Abstract

Remyelination failure in multiple sclerosis (MS) is associated with a migration/differentiation block of oligodendroglia. The reason for this block is highly debated. It could result from disease-related extrinsic or intrinsic regulators in oligodendroglial biology. To avoid confounding immune-mediated extrinsic effect, we used an immune-deficient mouse model to compare induced pluripotent stem cellderived oligodendroglia from MS and healthy donors following engraftment in the developing CNS. We show that the MS-progeny behaves and differentiates into oligodendrocytes to the same extent as controls. They generate equal amounts of myelin, with bona fide nodes of Ranvier, and promote equal restoration of their host slow conduction. MS-progeny expressed oligodendrocyte- and astrocyte-specific connexins and established functional connections with donor and host glia. Thus, MS oligodendroglia, regardless of major immune manipulators, are intrinsically capable of myelination and making functional axo-glia/glia-glia connections, reinforcing the view that the MS oligodendrocyte differentiation block is not from major intrinsic oligodendroglial deficits.

Remyelination occurs in multiple sclerosis (MS) lesions but its capacity decreases over time (13). Failed remyelination in MS leads to altered conduction followed by axon degeneration, which, in the long run, results in severe and permanent neurological deficits (4). MS lesions may or may not harbor immature oligodendroglia (oligodendrocyte progenitors and pre-oligodendrocytes), with these cells failing to differentiate into myelin-forming cells, suggesting that oligodendrocyte differentiation is blocked (57). So far, the mechanism underlying this block is poorly understood. It may result from adverse environmental conditions or the failed capacity of oligodendrocyte progenitors/pre-oligodendrocytes to migrate or mature efficiently into myelin-forming cells or even a combination of these conditions, all of which may worsen with aging. It has been shown that increasing remyelination either through manipulating the endogenous pool (8, 9) or by grafting competent myelin forming oligodendroglia (10, 11) or both (12) can restore the lost axonal functions, improve the clinical scores, and protect from subsequent axonal degeneration in experimental (13, 14) or clinical (3) settings.

There are multiple ways to investigate the oligodendroglial lineage in disease. Cells can be studied in postmortem tissue sections or purified from postmortem adult human brain for in vitro and transcriptomic/proteomic analysis. In this respect, in vitro experiments highlighted the heterogeneity of the adult human oligodendrocyte progenitor population in terms of antigen and microRNA expression, suggesting that remyelination in the adult human brain involves multiple progenitor populations (15). Moreover, single-cell transcriptomics characterized in detail the heterogeneity of human oligodendroglial cells, emphasizing changes in MS, with some subpopulations expressing disease-specific markers that could play a role in disease onset and/or aggravation (16, 17).

Yet, this MS signature could preexist or be acquired early at disease onset. Moreover, most of these MS postmortem analyses or experimental models cannot overlook the involvement of extrinsic factors such as immune factors that might add more complexity toward understanding the behavior of MS oligodenroglial cells.

Little is known about the biology of the MS oligodendroglial lineage, primarily due to the impossibility, for ethical reasons, to harvest oligodendroglial populations from patients and study the diseased cells and their matching controls in vitro or in vivo after cell transplantation. While cell-cell interactions and cell heterogeneity in diseased conditions generate more complexity when comparing control and pathological samples, the induced pluripotent stem cell (iPSC) technology provides a unique opportunity to study homogeneous populations of human oligodendroglial cells and gain further insights into monogenetic diseases and multifactorial diseases, such as MS. The iPSC technology has unraveled differences in oligodendroglia biology, in Huntingtons disease (18), and schizophrenia (19, 20), indicating that these cells can contribute autonomously to multifactorial diseases outcome. However, so far, little is known about the potential contribution of MS oligodendroglia to failed remyelination. While senescence affects iPSCneural precursor cells (NPCs) derived from patients with primary progressive MS (PPMS) (21), only few preliminary reports alluded to the fate of PPMS (22, 23) or relapsing-remitting (RRMS) (24) iPSC-derived oligodendroglia after experimental transplantation and did not study per se their capacity to differentiate into functional myelin-forming cells. We exploited a robust approach (25) to generate large quantities of iPSCs-derived O4+ oligodendroglial cells from skin fibroblasts (hiOLs) of three RRMS and three healthy subjects, including two monozygous twin pairs discordant for the disease. As a critical feature of the pluripotent-derived cells should be their ability to fully integrate and function in vivo, we compared the capacity of healthy and MS-hiOL derivatives to integrate and restore axo-glial and glial-glial functional interactions after engraftment in the developing dysmyelinated murine central nervous system (CNS). Our data show that in noninflammatory conditions, the intrinsic properties of iPSC-oligodendroglial cells to differentiate, myelinate, and establish functional cell-cell interactions in vivo are not altered in MS, making them candidates of interest for personalized drug/cell therapies as pluripotency maintains MS oligodendroglial cells in a genuine nonpathological state.

Fibroblasts were isolated from three control and three patients with MS and reprogrammed into iPSC. Pluripotent cells were differentiated into NPCs and further into O4+ hiOLs for 12 days in vitro under glial differentiation medium (GDM) conditions as previously described (25). hiOL cells were selected using flow cytometry for O4 before transplantation. Because our aim was to study the intrinsic properties of MS cells, we chose to engraft O4+ hiOLs in the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects.

We first questioned whether MS-hiOLs differed from control-hiOLs wild type (WT) in their capacity to survive and proliferate in vivo. To this aim, we grafted MS- and control-hiOLs in the forebrain of neonatal Shi/Shi:Rag2/ mice. MS cells engrafted (one injection per hemisphere) in the rostral forebrain, spread primarily through white matter, including the corpus callosum and fimbria, as previously observed using control human fetal (11, 26, 27) and iPSC (25, 28) progenitors. With time, cells also spread rostrally to the olfactory bulb and caudally to the brain stem and cerebellum (fig. S1). Examining engrafted brains at 8, 12, and 16 weeks postgraft (wpg), we found that MS-hiOLs expressing the human nuclear marker STEM101 and the oligodendroglial-specific transcription factor OLIG2 maintained a slow proliferation rate at all times (5 to 19% of STEM+ cells), with no difference in Ki67+ MS-hiOLs compared to control (Fig. 1, A and C). Moreover, immunostaining for cleaved Caspase3 at 8 wpg indicated that MS cells survived as well as control-hiOLs (Fig. 1, B and D). Evaluation of the cell density of human cells based on STEM positivity at each stage revealed no significant difference between grafted MS-hiOLs and control cells (fig. S2).

(A and C) Immunodetection of the human nuclei marker STEM101 (red) combined with OLIG2 (green) and the proliferation marker Ki67 (white) shows that a moderate proportion of MS-hiOLs sustains proliferation (empty arrowheads in the insets) following transplantation in their host developing brain, with no significant difference in the rate of proliferation between MS- and control-hiOLs over time. (B and D) Immunodetection of the apoptotic marker Caspase3 (green) indicates that MS-hiOLs survive as well as control-hiOLs 8 wpg. Two-way analysis of variance (ANOVA) followed by Tukeys multiple comparison or Mann-Whitney t tests were used for the statistical analysis (n = 3 to 4 mice per group). Error bars represent SEMs. H, Hoechst dye. Scale bars, 100 m.

Because MS-hiOLs and control cells proliferated and survived to the same extent, we next questioned whether their differentiation potential into mature oligodendrocytes could be affected. We used the human nuclei marker STEM101 to detect all human cells in combination with SOX10, a general marker for the oligodendroglial lineage, and CC1 as a marker of differentiated oligodendrocytes. We found that the number of MS oligodendroglial cells (SOX10+) increased slightly but significantly with time, most likely resulting from sustained proliferation (Fig. 2, A and B). Moreover, they timely differentiated into mature CC1+ oligodendrocytes with a fourfold increase at 12 wpg and a fivefold increase at 16 wpg when compared to 8 wpg and with no difference with control-hiOLs (Fig. 2, B and C).

(A) Combined immunodetection of human nuclei marker STEM101 (red) with CC1 (green) and SOX10 (white) for control (top) and MS-hiOLs (bottom) at 8, 12, and 16 wpg. (B and C) Quantification of SOX10+/STEM+ cells (B) and CC1+ SOX10+ over STEM+ cells (C). While the percentage of human oligodendroglial cells increased only slightly with time, the percentage of mature oligodendrocytes was significantly time regulated for both MS- and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 3 to 4 mice per group). Error bars represent SEMs. *P < 0.05 and ****P < 0.0001. Scale bar, 100 m.

The absence of abnormal MS-hiOL differentiation did not exclude a potential defect in myelination potential. We further investigated the capacity of MS-hiOLs to differentiate into myelin-forming cells. We focused our analysis on the core of the corpus callosum and fimbria. MS-hiOLs, identified by the human nuclear and cytoplasmic markers (STEM101 and STEM121), evolved from a bipolar to multibranched phenotype (Fig. 3A and fig. S3: compare 4 wpg to 8 and 12 wpg) and differentiated progressively into myelin basic proteinpositive (MBP+) cells associated, or not, with T-shaped MBP+ myelin-like profiles of increasing complexity (Fig. 3A and figs. S3 and S4B). Myelin-like profiles clearly overlapped with NF200+ axons (fig. S4A) and formed functional nodes of Ranvier expressing ankyrin G and flanked by paranodes enriched for CASPR (fig. S4B) or neurofascin (fig. S4C), as previously observed with control-hiOLs (25).

(A) Combined detection of human nuclei (STEM101) and human cytoplasm (STEM 121) (red) with MBP (green) in the Shi/Shi Rag2/ corpus callosum at 8, 12, and 16 wpg. General views of horizontal sections at the level of the corpus callosum showing the progressive increase of donor-derived myelin for control- (top) and MS- (bottom) hiOLs. (B) Evaluation of the MBP+ area over STEM+ cells. (C and D) Quantification of the percentage of (C) MBP+ cells and (D) MBP+ ensheathed cells. (E) Evaluation of the average sheath length (m) per MBP+ cells. No obvious difference was observed between MS and control-hiOLs. Two-way ANOVA followed by Tukeys multiple comparison tests were used for the statistical analysis of these experiments (n = 6 to 14 mice per group). Error bars represent SEMs. *P < 0.05, **P < 0.01, and ***P < 0.001. Scale bar, 200 m. See also figs. S3 and S5.

We further analyzed, in depth, the myelinating potential of MS-hiOLs, applying automated imaging and analysis, which provided multiparametric quantification of MBP as established in vitro (29) for each donor hiOL (three controls and three RRMS) at 4, 8, 12, 16, and 20 wpg in vivo (Fig. 3, B to D). We first examined the MBP+ surface area generated by the STEM+ cell population (Fig. 3B). While MS-hiOLs generated very low amount of myelin at 4 wpg, they generated significantly more myelin at 12, 16, and 20 wpg, with similar findings for control-hiOLs, highlighting the rapid progress in the percentage of myelin producing STEM+ cells in MS group over time. Detailed MBP+ surface area generated by the STEM+ cell population per donor is presented in fig. S5 and shows differences among hiOLs in the control and MS groups, respectively.

We also quantified the percentage of STEM+ cells expressing MBP and the percentage of MBP+ with processes associated with linear myelin-like features, which we called MBP+ ensheathed cells. Both parameters increased significantly with time for control-hiOLs, reaching a plateau at 16 wpg. The same tendency was achieved for MS-hiOLs with no significant differences between the control- and MS-hiOL groups (Fig. 3, C and D).

Myelin sheath length is considered to be an intrinsic property of oligodendrocytes (30). We analyzed this paradigm in our MS cohort at 12 and 16 wpg, time points at which sheaths were present at a density compatible with quantification. For those time points, we found that the average MS MBP+ sheath length was equivalent to that of control with 25.86 0.98 and 27.74 1.52 m for MS-hiOLs and 24.52 1.48 and 27.65 0.96 m for control-hiOLs at 12 and 16 wpg, respectively (Fig. 3F). In summary, our detailed analysis of immunohistochemically labeled sections indicates that MS-hiOLs did not generate abnormal amounts of myelin in vivo when compared to control-hiOLs.

Moreover, the myelinating potential of MS-hiOLs was further validated after engraftment in the developing spinal cord (4 weeks of age). Immunohistological analysis 12 wpg revealed that STEM+ cells not only populated the whole dorsal and ventral columns of the spinal cord with preferential colonization of white matter but also generated remarkable amounts of MBP+ myelin-like internodes that were found on multiple spinal cord coronal sections (fig. S6), thus indicating that their myelination potential was not restricted to only one CNS structure.

The presence of normal amounts of donor MBP+ myelin-like structures in the shiverer forebrain does not exclude potential structural anomalies. Therefore, we examined the quality of MS derived myelin at the ultrastructural level at 16 wpg in the Shi/Shi:Rag2/ forebrain. In the corpus callosum of both MS and control-hiOLs grafted mice, we detected numerous axons surrounded by electron dense myelin, which at higher magnification was fully compacted compared to the uncompacted shiverer myelin (Fig. 4, A to F) (25, 31). Moreover, MS myelin reached a mean g ratio of 0.76 1.15 comparable to that of control myelin (0.75 1.56) (Fig. 4G) and thus a similar myelin thickness. This argues in favor of (i) MS-hiOLs having the ability to produce normal compact myelin and thus its functional normality and (ii) a similar rate of myelination between the two groups and, consequently, an absence of delay in myelination for MS-hiOLs.

(A to F) Ultrastructure of myelin in sagittal sections of the core of the corpus callosum 16 wpg with control-hiOLs (A to C) and MS-hiOLs (D to F). (A and D) General views illustrating the presence of some electron dense myelin, which could be donor derived. (B, C, E, and F) Higher magnifications of control (B and C) and MS (E and F) grafted corpus callosum validate that host axons are surrounded by thick and compact donor derived myelin. Insets in (C) and (F) are enlargements of myelin and show the presence of the major dense line. No difference in compaction and structure is observed between the MS and control myelin. (G) Quantification of g-ratio revealed no significant difference between myelin thickness of axons myelinated by control- and MS-hiOLs. Mann-Whitney t tests were used for the statistical analysis of this experiment (n = 4 mice per group). Error bars represent SEMs. Scale bars, (A and D) 5 m , (B and E) 2 m, and (C and F) 500 nm [with 200 and 100 nm, respectively in (C) and (F) insets].

Myelin compaction has a direct impact on axonal conduction with slower conduction in shiverer mice compared to WT mice (10, 32). We therefore questioned whether newly formed MS-hiOLderived myelin has the ability to rescue the slow axon conduction velocity of shiverer mice in vivo (Fig. 5). As previously performed with fetal glial-restricted progenitors (11), transcallosal conduction was recorded in vivo at 16 wpg in mice grafted with MS- and control-hiOLs and compared with nongrafted shiverer and WT mice. As expected, conduction in nongrafted shiverer mice was significantly slower compared to WT mice. However, axon conduction velocity was rescued by MS-hiOLs and, to the same extent, by control-hiOLs.

(A) Scheme illustrating that intracallosal stimulation and recording are performed in the ipsi- and contralateral hemisphere, respectively. (B) N1 latency was measured following stimulation in different groups of Shi/Shi:Rag2/: intact or grafted with control or MS-hiOLs and WT mice at 16 wpg. MS-hiOLderived myelin significantly restored transcallosal conduction latency in Shi/Shi:Rag2/ mice to the same extent than control-derived myelin (P = 0.01) and close to that of WT levels. One-way ANOVA with Dunnetts multiple comparison test for each group against the group of intact Shi/Shi:Rag2/ was used. Error bars represent SEMs. *P < 0.05. (C) Representative response profiles for each group. Scales in Y axis is equal to 10 V and in the X axis is 0.4 ms.

Rodent oligodendrocyte progenitors and oligodendrocytes can be distinguished by cell stagespecific electrophysiological properties (33, 34). To assess the electrophysiological properties of oligodendroglial lineage cells derived from human grafted control- and MS-hiOLs, red fluorescent protein (RFP)hiOLs were engrafted in the Shi/Shi:Rag2/ forebrain and recorded with a K-gluconatebased intracellular solution in acute corpus callosum slices at 12 to 15 wpg (Fig. 6A). As previously described for rodent cells, hiOLs in both groups were identified by their characteristic voltage-dependent current profile recognized by the presence of inward Na+ currents and outwardly rectifying steady-state currents (Fig. 6B). We found that ~60 and ~44% of recorded cells were oligodendrocyte progenitors derived from MS and control progenies, respectively. No significant differences were observed in the amplitude of Na+ currents measured at 20 mV (Fig. 6D) or steady-state currents measured at +20 mV between MS- and control-derived oligodendrocyte progenitors (Isteady = 236.70 19.45 pA and 262.10 31.14 pA, respectively; P = 0.8148, Mann Whitney U test). We further confirmed the identity of these cells by the combined expression of SOX10 or OLIG2 with STEM101/121 and the absence of CC1 in biocytin-loaded cells (Fig. 6F, top). The remaining recorded cells (MS and control) did not show detectable Na+ currents after leak subtraction and were considered to be differentiated oligodendrocytes by their combined expression of SOX10, STEM101/121, and CC1 in biocytin-loaded cells (Fig. 6F, bottom). The I-V curve of these differentiated oligodendrocytes displayed a variable profile that gradually changed from voltage dependent to linear as described for young and mature oligodendroglial cells in the mouse (33). Figure 6C illustrates a typical linear I-V curve of fully mature MS-derived oligodendrocytes. No significant differences were observed in the amplitude of steady-state currents measured at +20 mV between MS- and control-derived oligodendrocytes (Fig. 6E). Overall, the electrophysiological profile of oligodendrocyte progenitors and oligodendrocytes derived from control and MS was equivalent and showed similar characteristics to murine cells (33, 34).

(A) Schematic representation of the concomitant Biocytin loading and recording of single RFP+ hiOL derivative in an acute coronal brain slice prepared from mice engrafted with hiOLs (control or MS) and analyzed at 12 to 14 wpg. (B and C) Currents elicited by voltage steps from 100 to +60 mV in a control-oligodendrocyte progenitor (B, left) and a MS-oligodendrocyte (C, left). Note that the presence of an inward Na+ current obtained after leak subtraction in the oligodendrocyte progenitor, but not in the oligodendrocyte (insets). The steady-state I-V curve of the oligodendrocyte progenitor displays an outward rectification (B, right) while the curve of the oligodendrocyte has a linear shape (C, right). (D) Mean amplitudes of Na+ currents measured at 20 mV in control and MS iPSCs-derived oligodendrocyte progenitors (n = 8 and n = 9, respectively, for four mice per condition; P = 0.743, Mann-Whitney U test). (E). Mean amplitudes of steady-state currents measured at +20 mV in control and patient differentiated iPSC-derived oligodendrocytes (n = 10 and n = 6 for 3 and four mice, respectively; P = 0.6058, Mann-Whitney U test). (F) A control iPSC-derived oligodendrocyte progenitor loaded with biocytin and expressing OLIG2, STEM101/121, and lacking CC1 (top) and an MS iPSCderived oligodendrocyte loaded with biocytin and expressing SOX10, CC1, and STEM101/121 (bottom). Scale bar, 20 m.

(A) Z-stack identifying a target and connected cell. One single grafted human RFP+ cell (per acute slice) was loaded with biocytin by a patch pipette and allowed to rest for 30 min. The white arrowheads and insets in (A) illustrate biocytin diffusion up to the donut-shaped tip of the human oligodendrocyte processes. Another biocytin-labeled cell (empty yellow arrowhead) was revealed at different morphological level indicating diffusion to a neighboring cell and communication between the two cells via gap junctions. (B and C) Split images of (A) showing the target (B) and connected (C) cell separately at different levels. Immunolabeling for the combined detection of the human markers STEM101/121 (red), OLIG2 (blue), and CC1 (white) indicated that the target cell is of human origin (STEM+) and strongly positive for OLIG2 and CC1, a mature oligodendrocyte, and that the connected cell is of murine origin (STEM-) and weakly positive for OLIG2 and CC1, most likely an immature oligodendrocyte. Scale bars, 30 m. See also fig. S7.

Studies with rodents have reported that oligodendrocytes exhibit extensive gap-junctional intercellular coupling between other oligodendrocytes and astrocytes (35). Whether oligodendrocytes derived from grafted human cells can be interconnected with cells in the adult host mouse brain was not known, and whether MS-hiOLs maintain this intrinsic property was also not addressed. Because biocytin can pass through gap junctions, we inspected biocytin-labeled cells for dye coupling (Figs. 6A and 7, A and B).

We found that two of seven MS-derived oligodendrocytes (~29%) and 5 of 21 control-derived oligodendrocytes (~24%) were connected with a single neighboring cell, which was either human or murine (Fig. 7), except in one case where three mouse cells were connected to the biocytin-loaded human cell. These findings reveal that gap junctional coupling can occur between cells from the same or different species, and MS-hiOLs can functionally connect to other glial cells to the same extent as their control counterparts.

To validate the presence of glial-glial interactions, we investigated whether the grafted hiOL-derived progeny had the machinery to be connected to one another via gap junctions. To this end, we focused on oligodendrocyte-specific Cx47 and astrocyte-specific Cx43 as Cx43/47 channels, which are important for astrocyte/oligodendrocyte cross talk during myelination and demyelination (36, 37). Combined immunolabeling for hNOGOA, CC1, OLIG2, and Cx47 revealed that MS-derived oligodendrocyte cell bodies and processes were decorated by Cx47+ gap junction plaques, which were often shared by exogenous MS-derived oligodendrocytes or by MS and endogenous murine oligodendrocytes (fig. S7A). In addition, colabeling exogenous myelin for MBP and Cx43 identified the presence of several astrocyte-specific Cx43 gap junction plaques between human myelin internodes, highlighting contact points between astrocyte processes and axons at the human-murine chimeric nodes of Ranvier (fig. S7B).

Last, colabeling of hNOGOA, with Cx47 and the astrocyte-specific Cx43, revealed coexpression of oligodendrocyte- and astrocyte-specific connexins at the surface of MS-derived oligodendrocyte cell bodies and at the level of T-shaped myelin-like structures (fig. S7C), thus implying connections between human oligodendrocytes and murine and/or human astrocytes, as a small proportion of the grafted hiOLs differentiated into astrocytes. Immunolabeling for human glial fibrillary acidic protein (GFAP), and Cx43 showed that these human astrocytes were decorated by Cx43+ aggregates, as observed in the host subventricular zone (fig. S8A).

Furthermore, immunolabeling for human GFAP, mouse GFAP, and Cx43 indicated that Cx43+ gap junctions were shared between human and mouse astrocytes as observed at the level of blood vessels (fig. S8B). These data validate interconnections between the grafted-derived human glia (MS and controls) with murine host glial cells and confirm their interconnection with the pan-glial network.

Two main hypotheses have been considered in understanding MS pathology and etiology: the outside-in hypothesis highlighting the role of immune regulators and environmental inhibitors as extrinsic key players in MS pathology and possibly its repair failure or the inside-out hypothesis pointing to the intrinsic characteristics of neuroglia including oligodendroglial cells as the main contributors in the MS scenario. Single-cell transcriptomic analysis revealed the presence of disease-specific oligodendroglia expressing susceptibility genes in MS brains (16) and altered oligodendroglia heterogeneity in MS (17). The question remains open as to whether these altered oligodendroglial phenotypes are acquired in response to the disease environment or whether they reflect intrinsic traits of the MS oligodendroglial population. On the other hand, the whole exome sequencing analysis in 132 patients from 34 multi-incident families identified 12 candidate genes of the innate immune system and provided the molecular and biological rational for the chronic inflammation, demyelination, and neurodegeneration observed in patients with MS (38) and revealed the presence of epigenetic variants in immune cells and in a subset of oligodendrocytes contributing to risk for MS (39).

While none of these hypotheses have been fully proven or rejected, research efforts for a better understanding of this multifactorial disease have continued. Impaired remyelination or oligodendrocyte differentiation block in MS is still considered a potentially disease-relevant phenotype (40, 41). Many histological and experimental studies suggest that impaired oligodendrocyte progenitor to oligodendrocyte differentiation may contribute to limited remyelination in MS, although some reports question the contribution of newly generated oligodendrocytes to remyelination (17, 42, 43). Understanding MS oligodendrocyte biology has been challenging mainly due to the following reasons: (i) oligodendroglial cells are not easily accessible to be studied in vivo; (ii) dynamic remyelination observed in patients with MS, which points to their individual remyelination potential, is inversely correlated with their clinical disability (3), highlighting even more complexity in oligodendrocyte heterogeneity between patients with MS; and (iii) exclusion of the role of immune system players in understanding MS oligodendrocyte biology being inevitable in most of clinical or experimental studies.

In such a complex multifactorial disease, one of the most accessible and applicable approaches to overcome these problems is the generation of large quantities of disease and control oligodendroglia using the iPSC technology, and to investigate their genuine behavior in vivo after engraftment in a B and T cellfree system. Using a very efficient reprogramming method (25), and the purely dysmyelinating Shi/Shi:Rag2/ mouse model to avoid confounding immune-mediated extrinsic effects, we show that MS-hiOLs derivatives survive, proliferate, migrate, and timely differentiate into bona fide myelinating oligodendrocytes in vivo as efficiently as their control counterparts. Nicaise and colleagues reported that iPSC-NPCs from PPMS cases did not provide neuroprotection against active CNS demyelination compared to control iPSC-NPCs (44) and failed to promote oligodendrocyte progenitor genesis due to senescence without affecting their endogenous capacity to generate myelin-forming oligodendrocytes (21, 22). However, their myelinating potential was not evaluated against control cells. Generation of iPSC-oligodendrocyte progenitors from patients with PPMS or RRMS has also been reported by other groups, yet with no evidence for their capacity to become functional oligodendrocytes in vivo (23, 24). Thus, so far, no conclusion could be made regarding the potential impact of disease severity (PPMS verses RRMS) on the functionality of the iPSC-derived progeny.

We compared side by side, and at different time points after engraftment, hiOLs from patients with RRMS and controls including two pairs of homozygous twins discordant for disease. We found no significant difference in their capacity to timely differentiate (according to the human tempo of differentiation) and efficiently myelinate axons in the shiverer mouse in terms of the percentage of MBP+ cells generated, amount of myelin produced, length of MBP+ sheaths, and the ultrastructure and thickness of myelin sheaths. MS-hiOLs also reconstructed nodes of Ranvier expressing nodal components key to their function. We not only verified that the grafted MS-hiOLs derivatives were anatomically competent but also established their functionality at the electrophysiological level using (i) in vivo recordings of transcallosal evoked potentials and (ii) ex vivo recordings of the elicited current-voltage curves of the grafted MS-hiOLs verses controls. Our data show that the grafted MS-hiOLs were able to rescue the established delayed latency of shiverer mice to the same extent as control cells, as previously reported for human fetal glial progenitors grafted in the same model (11). Moreover, at the single-cell level, MS-hiOLderived oligodendrocyte progenitors and oligodendrocytes did not harbor aberrant characteristics in membrane currents compared to control cells ex vivo. Thus, iPSC-derived human oligodendroglial cells shift their membrane properties with maturation as previously observed in vitro (45) and these properties are not impaired in MS.

The absence of differences among control and MS-derivatives might be due to different causes. One might consider that pluripotency induction could by in vitro manipulation, erase cell epigenetic traits and/or reverse cells to an embryonic state, and as a result, modulate their intrinsic characteristics. Yet, several reports have highlighted differences in the behavior of diseased iPSC-derived oligodendrocytes in comparison to those from healthy controls using the same technology in multifactorial diseases such as schizophrenia (19, 20), Huntingtons disease (18), and others (46). In this regard, direct reprogramming of somatic cells into the desired cell type, bypassing the pluripotent stage, could be an attractive alternative. However, so far only mouse fibroblasts have been successfully directly converted into oligodendroglial cells, and with relatively low efficiency (47, 48).

iPSCs were transduced with three transcription factors to generate hiOLs in a fast and efficient way (25). While we cannot rule out that the use of these three transcription factors may have obscured differences between MS and controls, results for controls are quite comparable to our previously published data based on human fetal oligodendrocyte progenitor engraftment in the Shi/Shi:Rag2/ developing forebrain (49) or fetal NPC engrafted in the Shi/Shi:Rag2/ demyelinated spinal cord (50), suggesting that transduction with the three transcription factors does not overly modify the behavior of the grafted human cells. It could also be argued that the absence of differences between control and MS monozygous twins is not surprising given their equal genetic background. Yet, comparing controls with nonsibling MS hiOLS (compare C1 with RRMS2 and RRMS3; C2 with RRMS1, RRMS2, and RRMS3; and C3 with RRMS1 and RRMS2) revealed no defect in myelination for MS cells as well.

Analysis of hiOLs from each donor showed differences within each group. This could result from phenotypic instability, heterogeneity among donors, or disease subtype. Yet, the clinical history of each patient suggests a certain homogeneity among the MS disease phenotype, all being RRMS. In addition, the equal survival and proliferation rates between both groups argue in favor of cell stability. These confounding observations sustain that differences in terms of myelination are most likely due to heterogeneity among individuals rather than phenotypic instability or disease subtype.

While most preclinical transplantation studies have focused on myelination potential as the successful outcome of axo-glia interactions, less is known about the capacity of the grafted cells to fulfill glial-glial interactions in the pan-glial syncytium, which could ensure maintenance of newly generated myelin (51) and cell homeostasis (52). Oligodendrocytes are extensively coupled to other oligodendrocytes and oligodendrocyte progenitors through the homologous gap junctions Cx47 (35). These intercellular interactions between competing oligodendroglial cells influence the number and length of myelin internodes and the initiation of differentiation (53, 54). Oligodendrocytes are also coupled to astrocytes through heterologous gap junctions such as Cx32/Cx30 and Cx47/Cx43 (55). Disruption of oligodendrocytes from each other and from astrocytes, i.e., deconstruction of pan-glial network, has been observed in experimental models of demyelination (unpublished data) and frequently reported in MS and neuromyelitis optica (37, 56, 57). Mutations in Cx47 and Cx32 result in developmental CNS and PNS abnormalities in leukodystrophies (58, 59). Moreover, experimental ablation of Cx47 results in aberrant myelination (60) and significantly abolished coupling of oligodendrocytes to astrocytes (35).

In view of the major role of Cx-mediated gap junctions among oligodendrocytes and between oligodendrocytes and astrocytes during myelin formation (55), we asked whether the MS-hiOL progeny was capable of making functional gap junctions with other glial cells, and integrating into the host panglial network. We show that grafted MS-hiOLs, in common with rodent oligodendrocytes, express Cx47 that was frequently shared not only between the human and murine oligodendrocytes (through Cx47-Cx47) but also in conjunction with the astrocyte Cx43 (via Cx47/Cx43). The dye-coupling study highlighted that MS-hiOLs, similar to control cells, were capable of forming functional gap junctions with neighbor murine or human glial cells, indicating that MS-hiOLs retained the intrinsic property, not only to myelinate host axons but also to functionally integrate into the host pan-glial network. While our study focused mainly on oligodendroglial cells, a small proportion of the grafted hiOLs differentiated into astrocytes expressing Cx43. These human astrocytes were detected associated with blood vessels or the subventricular zone, where they were structurally gap-junction coupled to mouse astrocytes as observed after engraftment of human fetal glial restricted progenitors (61).

Together, our data highlight that human skinderived glia retain characteristics of embryonic/fetal brainderived glia as observed for rodent cells (10). In particular, we show that MS-hiOLs timely differentiate into mature oligodendrocytes, functionally myelinate host axons and contribute to the human-mouse chimeric pan-glial network as efficiently as control-hiOLs. These observations favor a role for extrinsic rather than intrinsic oligodendroglial factors in the failed remyelination of MS. The International Multiple Sclerosis Genetics Consortium after analyzing the genomic map of more than 47,000 MS cases and 63,000 control subjects, implicated microglia, and multiple different peripheral immune cell populations in disease onset (62). Moreover, neuroinflammation appears to block oligodendrocyte differentiation and to alter their properties and thereby aggravate the autoimmune process (63). Furthermore, MS lymphocytes are reported to exhibit intrinsic capacities that drive myelin repair in a mouse model of demyelination (64). On the other hand, a recent study highlighted the presence of disease-specific oligodendroglia in MS (16, 17). However, it should be considered that most of the data in the later were collected using single nuclei RNA sequencing of postmortem tissues from MS or control subjects of different ages that were suffering from other disorders ranging from cancer to sepsis and undergoing various treatment, and so died for different reasons, that may have influenced the type or level of RNA expression by the cells. In addition, the presence of genetic variants that alter oligodendrocyte function in addition to that of immune cells was also found (39). While this oligodendrocyte dysfunction contributes to MS risk factor, whether it is involved in other aspects of MS such as severity, relapse rate, and rate of progression is not yet known.

Numerous factors may cause the failure of oligodendrocyte progenitor maturation comprising factors such as axonal damage and/or altered cellular and extracellular signaling within the lesion environment (65) without neglecting aged-related environmental and cellular changes (40). Although the cells generated in this study are more of an embryonic nature, and did not experienced the kind of inhibitory environment that is present in MS, our data provide valuable findings in the scenario of MS pathology highlighting that RRMS-hiOLs, regardless of major manipulators of the immune system, do not lose their intrinsic capacity to functionally myelinate and interact with other neuroglial cells in the CNS under nonpathological conditions. Whether RRMS-hiOLs or oligodendroglial cells directly reprogrammed from MS fibroblasts would behave similarly well, if challenged with neuropathological inflammatory conditions as opposed to conditions wherein the immune system is intact (presence of T and B cells), or whether they would reflect intrinsic aging properties will require further investigation.

In summary, our findings provide valuable insights not only into the biology of MS oligodendroglia but also their application for cell-based therapy and should contribute to the establishment of improved preclinical models for in vivo drug screening of pharmacological compounds targeting the oligodendrocyte progenitors, oligodendrocytes, and their interactions with the neuronal and pan-glial networks.

We examined side by side the molecular, cellular, and functional behavior of MS hiOLs with their control counterparts after their engraftment in a dysmyelinating animal model to avoid the effect of major immune modulators. We used three MS and three control hiOLs including two monozygous twin pairs discordant for the disease. We performed in vivo studies in mouse with sample size between three to six animals per donor/time point/assay required to achieve significant differences. Numbers of replicates are listed in each figure legend. Animals were monitored carefully during all the study time, and animal welfare criteria for experimentation were fully respected. All experiments were randomized with regard to animal enrollment into treatment groups. The same experimenter handled the animals and performed the engraftment experiments to avoid errors. The data were analyzed by a group of authors.

Shiverer mice were crossed to Rag2 null immunodeficient mice to generate a line of Shi/Shi:Rag2/ dysmyelinating-immunodeficient mice to (i) prevent rejection of the grafted human cells and allow detection of donor-derived WT myelin and (ii) investigate the original behavior of MS-derived oligodendrocytes in a B cell/T cellfree environment. Mice were housed under standard conditions of 12-hour light/12-hour dark cycles with ad libitum access to dry food and water at the ICM animal facility. Experiments were performed according to European Community regulations and INSERM ethical committee (authorization 75-348; 20/04/2005) and were approved by the local Darwin ethical committee.

Fibroblasts were obtained under informed consent from three control and three RRMS subjects including two monozygous twin pairs discordant for the disease. They were reprogrammed into iPSCs using the replication incompetent Senda virus kit (Invitrogen) according to manufacturers instructions. Table S1 summarizes information about the human cell lines used in this study. The study was approved by the local ethical committees of Mnster and Milan (AZ 2018-040-f-S, and Banca INSpe).

Human iPSCs were differentiated into NPC by treatment with small molecules as described (66, 67). Differentiation of NPCs into O4+ oligodendroglial cells used a poly-cistronic lentiviral vector containing the coding regions of the human transcription factors Sox10, Olig2, and Nkx6.2 (SON) followed by an IRES-pac cassette, allowing puromycin selection for 16 hours (25). For single-cell electrophysiological recordings, the IRES-pac cassette was replaced by a sequence encoding RFP. Briefly, human NPCs were seeded at 1.5 105 cells per well in 12-well plates, allowed to attach overnight and transduced with SON lentiviral particles and protamine sulfate (5 g/ml) in fresh NPC medium. After extensive washing, viral medium was replaced with glial induction medium (GIM). After 4 days, GIM was replaced by differentiation medium (DM). After 12 days of differentiation, cells were dissociated by accutase treatment for 10 min at 37C, washed with phosphate-buffered saline (PBS) and resuspended in PBS/0.5% bovine serum albumin (BSA) buffer, and singularized cells were filtered through a 70-m cell strainer (BD Falcon). Cells were incubated with mouse immunoglobulin M (IgM) antiO4-APC antibody (Miltenyi Biotech) following the manufacturers protocol, washed, resuspended in PBS/0.5% BSA buffer (5 106 cells/ml), and immediately sorted using a FACS Aria cell sorter (BD Biosciences). Subsequently, human O4+ hiOLs were frozen and stored in liquid nitrogen. Media details were provided in (25). hiOLS from each donor was assayed individually (no cell mix) and studied as follows for forebrain engraftment: immunohistochemistry (all donors, three to seven mice per time point), electron microscopy (C1 and RRMS1, four mice per donor at 16 wpg), in vivo electrophysiology (C1 and RRMS1, six mice per donor and eight mice per medium at 16 wpg), dye coupling, and ex-vivo electrophysiology (C1-RFP and RRMS3-RFP, six to seven mice per donor at 16 wpg). For spinal cord engraftment: immuno-histochemistry (C1 and RRMS3, 3 and 4 mice respectively at 12 wpg).

RRMS1: Disease duration at biopsy was 11 years. Started on Rebif 22 and switched to Rebif 44 because of relapses. Relapse was treated with bolus of cortisone 20 to 30 days before biopsy and then switched to natalizumab.

RRMS2: Disease duration at biopsy was 16 months. Relapse at disease onset. On Rebif 22 from disease onset until biopsy with no episodes. A new lesion was identified 3 months after biopsy. At the time of biopsy, the patient reported cognitive difficulties, no motor dysfunctions.

RRMS3: Disease duration at biopsy was 15 months. Relapse 6 months before biopsy with dysesthesias and hypoesthesia right thigh and buttock. Active lesion identified by magnetic resonance imaging at day 10. On Rebif smart 44 mcg, 50 days later, and skin biopsy 4 months later. A new gadolinium negative temporal lesion identified 2 months after biopsy and the patient switched to Tecfidera.

To assay hiOL contribution to forebrain developmental myelination, newborn Shi/Shi:Rag2/ pups (n = 148) were cryo-anesthetized, and control and RRMS hiOLs were transplanted bilaterally, rostral to the corpus callosum. Injections (1 l in each hemisphere and 105 cells/l) were performed 1 mm caudally, 1 mm laterally from the bregma, and to a depth of 1 mm as previously described (49, 68). Animals were sacrificed at 4, 8, 12, 16, and, when indicated, 20 wpg for immunohistological studies and at one time point for electron microscopy (16 wpg), ex vivo (12 to 15 wpg), and in vivo (16 wpg) electrophysiology.

To assay the fate of hiOLs in the developing spinal cord, 4-week-old mice (n = 4) were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) (Alcyon) and xylazine (10 mg/kg) (Alcyon) and received a single injection at low speed (1 l/2 min) of hiOLs (1 l, 105 cells/l) at the spinal cord thoracic level using a stereotaxic frame equipped with a micromanipulator and a Hamilton syringe. Animals were sacrificed at 12 wpg for immunohistological studies.

Immunohistochemistry. Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 3 to 6 per group, donor and time point) were sacrificed by transcardiac perfusion-fixation with 4% paraformaldehyde in PBS. Tissues were postfixed in the same fixative for 1 hour and incubated in 20% sucrose in 1 PBS overnight before freezing at 80C. Serial horizontal brain and spinal cord cross sections of 12 m thickness were performed with a cryostat (CM3050S, Leica). Transplanted hiOLs were identified using anti-human cytoplasm [1:100; STEM121; Takara, Y40410, IgG1], anti-human nuclei (1:100; STEM101; Takara, Y40400, IgG1), and anti-human NOGOA (1:50; Santa Cruz Biotechnology, sc-11030, goat) antibodies. In vivo characterization was performed using a series of primary antibodies listed in tableS2. For MBP staining, sections were pretreated with ethanol (10 min, room temperature). For glial-glial interactions, oligodendrocyte-specific connexin was detected with anti-connexin 47 (1:200; Cx47; Invitrogen, 4A11A2, IgG1) and astrocyte-specific connexin, with anti-connexin 43 (1:50; Cx43; Sigma-Aldrich, C6219, rabbit), and sections were pretreated with methanol (10 min, 20C). Secondary antibodies conjugated with fluorescein isothiocyanate, tetramethyl rhodamine isothiocyanate (SouthernBiotech), or Alexa Fluor 647 (Life Technologies) were used, respectively, at 1:100 and 1:1000. Biotin-conjugated antibodies followed by AMCA AVIDIN D (1:20; Vector, A2006). Nuclei were stained with 4,6-diamidino-2-phenylindole (DAPI) (1 g/ml; Sigma-Aldrich) (1:1000). Tissue scanning, cell visualization, and imaging were performed with a Carl Zeiss microscope equipped with ApoTome 2.

Electron microscopy. For electron microscopy, Shi/Shi:Rag2/ mice grafted with control and RRMS hiOLs (n = 4 per group) were perfused with 1% PBS followed by a mixture of 4% paraformaldehyde/5% glutaraldehyde (Electron Microscopy Sciences) in 1% PBS. After 2-hour postfixation in the same solution, 100-m-thick sagittal sections were cut and fixed in 2% osmium tetroxide (Sigma-Aldrich) overnight. After dehydration, samples were flat-embedded in Epon. Ultra-thin sections (80 nm) of the median corpus callosum were examined and imaged with a HITACHI 120 kV HT-7700 electron microscope.

Electrophysiological recordings were performed in mice grafted with MS- and control-hiOLs, and compared with nongrafted intact or medium injected Shi/Shi:Rag2/ mice and WT mice 16 weeks after injection (n = 4 to 6 per group) as described (11). Briefly mice were anesthetized with 2 to 4% isoflurane performed under analgesia (0.1 mg/kg buprecare) and placed in a stereotaxic frame (D. Kopf, Tujunga, CA, USA). Body temperature was maintained at 37C by a feedback-controlled heating blanket (CMA Microdialysis). Electrical stimulation (0.1 ms at 0 to 0.1 mA) was applied using a bipolar electrode (FHC- CBBSE75) inserted to a depth of 200 m into the left cortex at 2 mm posterior to bregma and 3 mm from the midline. At the same coordinates in the contralateral hemisphere, homemade electrodes were positioned for recording local field potentials (LFPs) generated by transcallosal electric stimulation. Electrical stimulation and evoked LFPs were performed by the data acquisition system apparatus (Neurosoft, Russia), and signals were filtered at 0.01 to 1 000 Hz. Each response latency (in ms) was measured as the time between the onset of stimulus artifact to the first peak for each animal. A ground electrode was placed subcutaneously over the neck.

Slice preparation and recordings. Acute coronal slices (300 m) containing corpus callosum were made from Shi/Shi:Rag2/ mice grafted with control (n = 7) and RRMS (n = 6) RFP+ hiOLs. They were prepared from grafted mice between 12 and 15 wpg as previously described (69). Briefly, slices were performed in a chilled cutting solution containing 93 mM N-methyl-d-glucamine, 2.5 mM KCl, 1.2 mM NaH2PO4, 30 mM NaHCO3, 20 mM Hepes, 25 mM glucose, 2 mM urea, 5 mM Na-ascorbate, 3 mM Na-pyruvate, 0.5 mM CaCl2, and 10 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2) and kept in the same solution for 8 min at 34C. Then, they were transferred for 20 min to solution at 34C containing 126 mM NaCl, 2.5 mM KCl, 1.25 mM NaH2PO4, 26 mM NaHCO3, 20 mM glucose, 5 mM Na-pyruvate, 2 mM CaCl2, and 1 mM MgCl2 (pH 7.3 to pH 7.4; 95% O2 and 5% CO2). Transplanted RFP+ hiOLs were visualized with a 40 fluorescent water-immersion objective on an Olympus BX51 microscope coupled to a CMOS digital camera (TH4-200 OptiMOS) and an light-emitting diode light source (CoolLed p-E2, Scientifica, UK) and recorded in voltage-clamp mode with an intracellular solution containing 130 mM K-gluconate, 0.1 mM EGTA, 2 mM MgCl2, 10 mM Hepes, 10 mM -aminobutyric acid, 2 mM Na2-adenosine 5-triphosphate, 0.5 mM Na-guanosine 5-triphosphate, 10 mM Na2-phosphocreatine, and 5.4 mM biocytin (pH 7.23). Holding potentials were corrected by a junction potential of 10 mV. Electrophysiological recordings were performed with Multiclamp 700B and Pclamp10.6 software (Molecular Devices). Signals were filtered at 3 kHz, digitized at 10 kHz, and analyzed off-line.

Immunostainings and imaging of recorded slices. For analysis of recorded cells, one single RFP+ cell per hemisphere was recorded in a slice and loaded with biocytin for 25 min in whole-cell configuration. After gently removing the patch pipette, biocytin was allowed to diffuse for at least 10 min before the slice was fixed 2 hours in 4% paraformaldehyde at 4C. Then, the slice was rinsed three times in PBS for 10 min and incubated with 1% Triton X-100 and 10% normal goat serum (NGS) for 2 hours. After washing in PBS, slices were immunostained for SOX10, CC1, and STEM101/121. Tissues were incubated with primary antibodies for 3 days at 4C. Secondary antibodies were diluted in 2% NGS and 0.2% Triton X-100. Tissues were incubated with secondary antibodies for 2 hours at room temperature. Biocytin was revealed with secondary antibodies using DyLight-488 streptavidin (Vector Laboratories, Burlingame, USA, 1:200). Images of biocytin-loaded cells were acquired either with a Carl Zeiss microscope equipped with ApoTome 2 or a LEICA SP8 confocal microscope (63 oil objective; numerical aperture, 1.4; 0.75-m Z-step) and processed with National Institutes of Health ImageJ software (70).

We adapted the heuristic algorithm from (29) to identify STEM+ MBP+ OLs in tissue sections. The foundations of the quantitative method remained the same. A ridge-filter extracted sheath-like objects based on intensity and segments associated to cell bodies using watershed segmentation. Two additional features adapted the workflow beyond its original in vitro application. First, we added functionality to allow colocalization of multiple fluorescent stains, as we needed to quantify triple positive STEM+/MBP+/DAPI+ cell objects. Second, because oligodendrocyte sheaths are not parallel and aligned in situ as they are in dissociated nanofiber cell cultures, we adapted the algorithm to report additional metrics about MBP production locally and globally that do not rely on the dissociation of sheaths in dense regions.

Cell nuclei were identified using watershed segmentation of DAPI+ regions and then colocalized pixel-wise with STEM+ objects. The DAPI+ nuclei were then used as local minima to seed a watershed segmentation of the STEM+ stain to separate nearby cell bodies. Last, the identified STEM+ cell bodies were colocalized with overlapping MBP+ sheath-like ridges to define ensheathed cells. We reported the area of MBP overlapping with STEM fluorescence in colocalized regions associated with individual cells, as well as the number of single, double, and triple fluorescently labeled cells. In addition, different cellular phenotypes were noted in situ that were then captured with the adapted algorithm. Qualitatively, we observed cells with expansive MBP production without extended linear sheath-like segments that were not observed in previous applications of the algorithm. These cells were denoted as tuft cells, and were quantitatively defined as STEM+/MBP+/DAPI+ cells without fluorescent ridges that could be identified as extended sheath-like objects.

The myelination potential of three control and 3 MS hiOLs was evaluated at 4, 8, 12, 16, and 20 wpg (n = 2 to 7 per line and per time point; n = 6 to 14 per time point). For each animal, six serial sections at 180-m intervals were analyzed. The percentage of MBP+ cells (composed of ensheathed or tuft cells) was evaluated. Total MBP+ area per STEM+ cells and the average length of MBP+ sheaths per MBP+ cells were analyzed.

Cell survival, proliferation, and differentiation in vivo. The number of STEM101+ grafted cells expressing Caspase3, or Ki67, or SOX10 and CC1 was quantified in the core of the corpus callosum at 8, 12, and 16 wpg. For each animal (n = 3 per group), six serial sections at 180-m intervals were analyzed. Cell counts were expressed as the percentage of total STEM101+ cells.

Myelination by electron microscopy. G ratio (diameter of axon/diameter of axon and myelin sheath) of donor-derived compact myelin was measured as previously described (10). Briefly, the maximum and minimum diameters of a given axon and the maximum and minimum axon plus myelin sheath diameter were measured with the ImageJ software at a magnification of 62,000 for a minimum of 70 myelinated axons per animal. Data were expressed as the mean of the maximal and minimal values for each axon for mice from each group (n = 4 mice per group). Myelin compaction was confirmed at a magnification of 220,000.

Data are presented as means + SEM. Statistical significance was determined by two-tailed Mann Whitney U test when comparing two statistical groups, and with one-way or two-way analysis of variance (ANOVA) followed by Tukeys or Dunnetts (in vivo electrophysiology) multiple comparison tests for multiple groups. Because electrophysiological data in brain slices do not follow a normal distribution after a DAgostino-Pearson normality test, we also performed two-tailed Mann-Whitney U test for comparison between groups. Statistics were done in GraphPad Prism 5.00 and GraphPad Prism 8.2.1 (GraphPad Software Inc., USA). See the figure captions for the test used in each experiment.

Acknowledgments: Funding: This work was supported by the Progressive MS Alliance [PMSA; collaborative research network PA-1604-08492 (BRAVEinMS)] to G.M., J.P.A., A.B.-V.E., and T.K., the National MS Society (NMSS RG-1801-30020 to T.K. and A.B.-V.E.), INSERM and ICM grants to A.B.-V.E., the German Research Foundation (DFG CRC-TR-128B07 to T.K.), and the Italian Multiple Sclerosis Foundation (FISM) (project no. Neural Stem Cells in MS to G.M.). M.C.A. was supported by grants from Fondation pour laide la recherche sur la Sclrose en Plaques (ARSEP) and a sub-award agreement from the University of Connecticut with funds provided by grant no. RG-1612-26501 from National Multiple Sclerosis Society. During this work, S.M. was funded by European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). B.G.-D. and M.J.F.L. were supported by the PMSA, PA-1604-08492 and the National MS Society (RG-1801-30020), respectively. B.M.-S. was supported by a Ph.D. fellowship from the French Ministry of Research (ED BioSPC). A.B. and M.C.A. thank respective imaging facilities, ICM Quant and IPNP NeurImag and their respective funding sources Institut des Neurosciences Translationnelles ANR-10-IAIHU-06 Fondation Leducq. Author contributions: Conceptualization: S.M. and A.B.-V.E. Methodology: S.M., L.S., B.M.-S., Y.K.T.X., B.G.-D., M.J.F.L., D.R., L.O., K.-P.K., H.R.S., J.P.A., T.K., G.M., T.E.K., M.C.A., and A.B.V.-E. Formal analysis: S.M., B.M-S., Y.K.T.X., M.C.A., and A.B.-V.E. Writing: S.M. and A.B.V.-E, with editing and discussion from all coauthors Funding acquisition: S.M. and A.B.V.-E. Supervision: A.B.V.-E. Competing interests: T.K. has a pending patent application for the generation of human oligodendrocytes. The authors declare that they have no other 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.

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Multiple sclerosis iPS-derived oligodendroglia conserve their properties to functionally interact with axons and glia in vivo - Science Advances

The Stem Cell-Derived Cells market to Scale new heights in the next decade – Khabar South Asia

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

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The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

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North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

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The Stem Cell-Derived Cells market to Scale new heights in the next decade - Khabar South Asia

The Stem Cell-Derived Cells Market to witness explicit growth from 2019 and 2029 – The Haitian-Caribbean News Network

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

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The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

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North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

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The Stem Cell-Derived Cells Market to witness explicit growth from 2019 and 2029 - The Haitian-Caribbean News Network

Stem Cells Market Research Provides an In-Depth Analysis on the Future Growth Prospects and Industry Trends Adopted by the Competitors | (2020-2027),…

Stem Cells Market Overview:

Reports and Data has recently published a new research study titled Global Stem Cells Market that offers accurate insights for the Stem Cells market formulated with extensive research. The report explores the shifting focus observed in the market to offer the readers data and enable them to capitalize on market development. The report explores the essential industry data and generates a comprehensive document covering key geographies, technology developments, product types, applications, business verticals, sales network and distribution channels, and other key segments.

The global Stem Cells market is forecasted to grow at a rate of 8.4% from USD 9.35 billion in 2019 to USD 17.78 billion in 2027.

The report is further furnished with the latest market changes and trends owing to the global COVID-19 crisis. The report explores the impact of the crisis on the market and offers a comprehensive overview of the segments and sub-segments affected by the crisis. The study covers the present and future impact of the pandemic on the overall growth of the industry.

Get a sample of the report @ https://www.reportsanddata.com/sample-enquiry-form/2981

Competitive Landscape:

The global Stem Cells market is consolidated owing to the existence of domestic and international manufacturers and vendors in the market. The prominent players of the key geographies are undertaking several business initiatives to gain a robust footing in the industry. These strategies include mergers and acquisitions, product launches, joint ventures, collaborations, partnerships, agreements, and government deals. These strategies assist them in carrying out product developments and technological advancements.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

Thermo Fisher Scientific, Agilent Technologies, Illumina, Inc., Qiagen, Oxford Nanopore Technologies, Eurofins Scientific, F. Hoffmann-La Roche, Danaher Corporation, Bio-Rad Laboratories, and GE Healthcare.

An extensive analysis of the market dynamics, including a study of drivers, constraints, opportunities, risks, limitations, and threats have been studied in the report. The report offers region-centric data and analysis of the micro and macro-economic factors affecting the growth of the overall Stem Cells market. The report offers a comprehensive assessment of the growth prospects, market trends, revenue generation, product launches, and other strategic business initiatives to assist the readers in formulating smart investment and business strategies.

To read more about the report, visit @ https://www.reportsanddata.com/report-detail/stem-cells-market

Product Outlook (Revenue, USD Billion; 2017-2027)

Technology Outlook (Revenue, USD Billion; 2017-2027)

Therapy Outlook (Revenue, USD Billion; 2017-2027)

Application Outlook (Revenue, USD Billion; 2017-2027)

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Key Coverage in the Stem Cells Market Report:

Thank you for reading our report. Please get in touch with us if you have any queries regarding the report or its customization. Our team will make sure the report is tailored to meet your requirements.

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Stem Cells Market Research Provides an In-Depth Analysis on the Future Growth Prospects and Industry Trends Adopted by the Competitors | (2020-2027),...

Stem Cells Market 2020: Rising with Immense Development Trends across the Globe by 2027 – The Market Feed

Stem Cells Market Overview:

Reports and Data has recently published a new research study titled Global Stem Cells Market that offers accurate insights for the Stem Cells market formulated with extensive research. The report explores the shifting focus observed in the market to offer the readers data and enable them to capitalize on market development. The report explores the essential industry data and generates a comprehensive document covering key geographies, technology developments, product types, applications, business verticals, sales network and distribution channels, and other key segments.

The report is further furnished with the latest market changes and trends owing to the global COVID-19 crisis. The report explores the impact of the crisis on the market and offers a comprehensive overview of the segments and sub-segments affected by the crisis. The study covers the present and future impact of the pandemic on the overall growth of the industry.

Get a sample of the report @ https://www.reportsanddata.com/sample-enquiry-form/2981

Competitive Landscape:

The global Stem Cells market is consolidated owing to the existence of domestic and international manufacturers and vendors in the market. The prominent players of the key geographies are undertaking several business initiatives to gain a robust footing in the industry. These strategies include mergers and acquisitions, product launches, joint ventures, collaborations, partnerships, agreements, and government deals. These strategies assist them in carrying out product developments and technological advancements.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

Celgene Corporation, ReNeuron Group plc, Virgin Health Bank, Biovault Family, Mesoblast Ltd., Caladrius, Opexa Therapeutics, Inc., Precious Cells International Ltd., Pluristem, and Neuralstem, Inc., among others.

An extensive analysis of the market dynamics, including a study of drivers, constraints, opportunities, risks, limitations, and threats have been studied in the report. The report offers region-centric data and analysis of the micro and macro-economic factors affecting the growth of the overall Stem Cells market. The report offers a comprehensive assessment of the growth prospects, market trends, revenue generation, product launches, and other strategic business initiatives to assist the readers in formulating smart investment and business strategies.

To read more about the report, visit @ https://www.reportsanddata.com/report-detail/stem-cells-market

Product Outlook (Revenue, USD Billion; 2017-2027)

Technology Outlook (Revenue, USD Billion; 2017-2027)

Therapy Outlook (Revenue, USD Billion; 2017-2027)

Application Outlook (Revenue, USD Billion; 2017-2027)

Request a discount on the report @ https://www.reportsanddata.com/discount-enquiry-form/2981

Key Coverage in the Stem Cells Market Report:

Thank you for reading our report. Please get in touch with us if you have any queries regarding the report or its customization. Our team will make sure the report is tailored to meet your requirements.

Take a look at other reports from Reports and Data on PR Newswire:

Hydroxycitronellal Market: Hydroxycitronellal Market To Reach USD 192.7 Million By 2027

Sterile Filtration Market: Sterile Filtration Market To Reach USD 8.48 Billion By 2027 | CAGR: 7.7%

Tissue Diagnostics Market: Tissue Diagnostics Market To Reach USD 5.02 Billion By 2027

UV-C Robot Market: UV-C Robot Market to Reach USD 1.46 Billion by 2027

About Us:

Our in-house experts assist our clients with advice based on their proficiency in the market that helps them in creating a compendious database for the clients. Our team offers expert insights to clients to guide them through their business ventures. We put in rigorous efforts to keep our clientele satisfied and focus on fulfilling their demands to make sure that the end-product is what they desire. We excel in diverse fields of the market and with our services extending to competitive analysis, research and development analysis, and demand estimation among others, we can help you invest your funds in the most beneficial areas for research and development. You can rely on us to provide every significant detail you might need in your efforts to make your business flourish.

Contact Us:

John Watson

Head of Business Development

Reports and Data|Web:www.reportsanddata.com

Direct Line:+1-212-710-1370

E-mail:[emailprotected]

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Originally posted here:
Stem Cells Market 2020: Rising with Immense Development Trends across the Globe by 2027 - The Market Feed

U.S. engineering firms ride on waves of innovation – Building Design + Construction

Last year, SSOE Group saved an automotive client more than $250,000 by streamlining how data from the clients manufacturing structures were gathered, using laser scanning, innovative workflows, and technology that converts point clouds to Revit models that can be imported to structural analysis software.

Innovation continues to be engineering firms best foot forward to remain competitive and relevant. And sometimes, innovation is resolutely basic: For a series of manhole inspections it performed for Carnegie Mellon University, Wiley|Wilson attached a camera controlled by a smartphone app to a 9-foot-long selfie stick for 360-degree information capture. KCI Technologies piloted AM Gradiometry technology, a subsurface investigation methodology that harnesses the power of AM-band radio to identify and map underground infrastructure and anomalies.

Admittedly, most other innovations engineers came up with werent as rudimentary. Jensen Hughes launched a new software program, HazAdvisr, that quickly categorizes chemical hazards and applies them to a project to achieve compliance, eliminating the need for time-consuming and often error-prone classification done by hand. AECOMs patented water treatment solution, De-Fluoro, destroys a globally pervasive emerging contaminant Perfluorooctanoic Acid (PFAS), and optimizes infrastructure upgrades.

Thornton Tomasetti launched Beacon, an embodied carbon measurement tool that allows structural engineers to understand and manage embodied carbon optimization. And CDM Smith recently collaborated with Autodesk to develop the Rapid Energy Modeling tool, an integrated desktop application that enables energy managers and planners to conduct energy analyses at facilities without deploying physical resources onsite. Syska Hennessy was of the same mindset when it established a process to perform remote commissioning, punch-lists, and onsite field work virtually.

Engineers are more frequently being called upon for solutions that reduce their customers risks. For example, Affiliated Engineers Inc.s resilience planning and design service features a tool that addresses climate change for the owners project location, characterizes the risk of failure to engineering systems should the identified potential disaster scale hazardous event(s) occur, develops adaptation and mitigation strategies, and presents this information in rich graphic form to the owner and design team.

Other innovations are designed as platforms for collaboration and greater efficiency. KLH Engineers created a series of custom Revit add-ins geared toward eliminating repetitive, rules-based tasks and providing the engineers with information they need to make informed decisions early in a project. And PBS Engineers is using 3D cameras to document the existing conditions of spaces during the initial site surveys. This process allows the team to have an accurate representation of the MEP conditions for a more coordinated design set.

These innovations emerged at a time when engineering firms were adding to their practice menus, and the sector continued to consolidate. Last October, IPSIntegrated launched a new service called CarTon, a complete cell and gene therapy operational readiness solution. This bundled service offering focuses on getting compliant cell and gene therapy products to market. Bernhards Energy-as-a-Service solutions offer healthcare clients alternative financing and project delivery methods that are designed to reduce cost structure and increase operational margins.

Burns & McDonnell hired a dozen professionals to expand services in the life sciences industry, collectively adding more than 200 years of additional design and construction experience in the pharmaceutical, biotech, animal health, medical device, and gene therapy sectors. EAPC Architects is now offering Entitlement services that process land development cases for rezoning properties, obtaining special permits and conditional uses for a specific land use. HPE Data Center relaunched its consulting practice in the U.S., Thailand, and Indonesia. Davis, Bowen & Friedel introduced the addition of in-house unmanned aerial vehicle (UAV) drone services. And DeSimone Consulting Engineers initiated a Risk Management Services practice.

For its industrializing colocation and hyperscale clientele, EYP Mission Critical rolled out a suite of formalized services focused on the adaptation of standardized designs for new paradigms, modular containerized implementation, tenant fit-out/retrofit, and optimization and operational efficiency in power, space, and cooling.

The coronavirus pushed several firms into new areas. Milhouse Engineerings environmental experts developed a method for sanitization that combines a specially atomized fog and a three-stage HEPA air filtration system. NV5 Global offered a suite of COVID-19 support services. To support business continuity, its COVID-19 facility health and safety services provide site-specific deep cleaning protocols and training of cleaning staff to minimize risk of exposures. In California, the firm offered third-party building inspections and plan reviews in municipalities that closed their building departments during the outbreak. NV5s MEP engineering and commissioning group supports remote field hospitals and facility renovations.

NV5 Global made nine strategic acquisitions in 2019 that added 1,100 employees, enhanced service offerings in the environmental, technology, infrastructure, and energy markets; and broadened its geographic coverage.

In 2019, IMEG Corp. acquired five firms and 10 new office locations. These acquisitions brought its employee count to 1,500 employees across nearly 50 locations. In 2019, Dewberry acquired California-based Drake Haglan and Associates, an 80-person firm serving private- and public-sector clients. P2S Inc. acquired Muni-Fed, an energy and civil engineering consulting firm, in Q4 2019. In August 2019, TLC Engineering acquired an FP/LS firm that doubled TLCs revenue in this discipline. It also acquired a Chicago-based MEP firm that became its 15th location. And with the addition of design firms studio951 and EPOCH during the fourth quarter of 2019, Shive-Hattery expanded into two new markets: Lincoln, Neb., and South Bend, Ind.

Other firms saw operational opportunities in the virtual world: For instance, Ross & Baruzzini converted its entire IT infrastructure to Amazon Web Services cloud and virtual desktop services.

Last year, 31% of Desimones revenue came from green building and sustainability projects. And it was easy to forget, during a pandemic, that carbon neutrality remains a long-range goal for the built environment.

Morrison Hershfield, in collaboration with Humber College and project partners, completed a holistic deep energy retrofit of an aging Humber Building NX, making it the first existing building retrofit in Canada to achieve Zero Carbon Building-Design Certification from the Canada Green Building Council. In Spokane, Wash., McKinstry developed and designed Catalyst, a five-story, 159,000-sf cross-laminated timber (CLT) building whose goal is to be one of the largest zero-energy and one of the first zero-carbon buildings in North America.

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U.S. engineering firms ride on waves of innovation - Building Design + Construction

The Stem Cell-Derived Cells market to be in conjunction to growth from 2020 to 2030 – PRnews Leader

Stem cell-derived cells are ready-made human induced pluripotent stem cells (iPS) and iPS-derived cell lines that are extracted ethically and have been characterized as per highest industry standards. Stem cell-derived cells iPS cells are derived from the skin fibroblasts from variety of healthy human donors of varying age and gender. These stem cell-derived cells are then commercialized for use with the consent obtained from cell donors. These stem cell-derived cells are then developed using a complete culture system that is an easy-to-use system used for defined iPS-derived cell expansion. Majority of the key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

To remain ahead of your competitors, request for a sample[emailprotected]

https://www.persistencemarketresearch.com/samples/28780

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

To receive extensive list of important regions, Request Methodology here @

https://www.persistencemarketresearch.com/methodology/28780

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

You Can Request for TOC[emailprotected]

https://www.persistencemarketresearch.com/toc/28780

Explore Extensive Coverage of PMR`s

Life Sciences & Transformational HealthLandscape

About us:

Persistence Market Research (PMR) is a third-platform research firm. Our research model is a unique collaboration of data analytics andmarket research methodologyto help businesses achieve optimal performance.

To support companies in overcoming complex business challenges, we follow a multi-disciplinary approach. At PMR, we unite various data streams from multi-dimensional sources. By deploying real-time data collection, big data, and customer experience analytics, we deliver business intelligence for organizations of all sizes.

Our client success stories feature a range of clients from Fortune 500 companies to fast-growing startups. PMRs collaborative environment is committed to building industry-specific solutions by transforming data from multiple streams into a strategic asset.

Contact us:

Naved BegPersistence Market ResearchAddress 305 Broadway, 7th Floor, New York City,NY 10007 United StatesU.S. Ph. +1-646-568-7751USA-Canada Toll-free +1 800-961-0353Sales[emailprotected]Websitehttps://www.persistencemarketresearch.com

Excerpt from:
The Stem Cell-Derived Cells market to be in conjunction to growth from 2020 to 2030 - PRnews Leader

Stem Cell-Derived Cells Market to Expand at a Healthy CAGR of XX% Between and 2019 2029 – Eurowire

Stem Cell-Derived Cells Market report 2018, discusses various factors driving or restraining the market, which will help the future market to grow with promising CAGR. The Stem Cell-Derived Cells Market research Reports offers an extensive collection of reports on different markets covering crucial details. The report studies the competitive environment of the Stem Cell-Derived Cells Market is based on company profiles and their efforts on increasing product value and production.

This Report covers the manufacturers data, including: shipment, price, revenue, gross profit, interview record, business distribution etc., these data help the consumer know about the competitors better. This report also covers all the regions and countries of the world, which shows a regional development status, including market size, volume and value, as well as price data.

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The report analyzes the market of Stem Cell-Derived Cells by main manufactures and geographic regions. The report includes Stem Cell-Derived Cells definitions, classifications, applications, and industry chain structure, development trends, competitive landscape analysis, and key regions development and market status.

By Market Players:

key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

The report covers exhaustive analysis on:

Regional analysis includes

Report Highlights:

Reasons to Purchase This Report:

Market analysis for the global Stem Cell-Derived Cells Market, with region-specific assessments and competition analysis on a global and regional scale.

Analyzing various perspectives of the market with the help of Porters five forces analysis

Which textile, raw material, and application is expected to dominate the market

Which country is expected to witness the fastest growth during the forecast period?

Identify the latest developments, market shares and strategies employed by the major market players.

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The key insights of the Stem Cell-Derived Cells market report:

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Stem Cell-Derived Cells Market to Expand at a Healthy CAGR of XX% Between and 2019 2029 - Eurowire

Stem Cell-Derived Cells Market Forecasted To Surpass The Value Of US$ XX Mn/Bn By 2019 – 2029 – Stock Market Funda

In this report, the global Stem Cell-Derived Cells market is valued at USD XX million in 2019 and is projected to reach USD XX million by the end of 2025, growing at a CAGR of XX% during the period 2019 to 2025.

Persistence Market Research recently published a market study that sheds light on the growth prospects of the global Stem Cell-Derived Cells market during the forecast period (20XX-20XX). In addition, the report also includes a detailed analysis of the impact of the novel COVID-19 pandemic on the future prospects of the Stem Cell-Derived Cells market. The report provides a thorough evaluation of the latest trends, market drivers, opportunities, and challenges within the global Stem Cell-Derived Cells market to assist our clients arrive at beneficial business decisions.

The Stem Cell-Derived Cells market report firstly introduced the basics: definitions, classifications, applications and market overview; product specifications; manufacturing processes; cost structures, raw materials and so on. Then it analyzed the worlds main region market conditions, including the product price, profit, capacity, production, supply, demand and market growth rate and forecast etc. In the end, the Stem Cell-Derived Cells market report introduced new project SWOT analysis, investment feasibility analysis, and investment return analysis.

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Resourceful insights enclosed in the report:

The major players profiled in this Stem Cell-Derived Cells market report include:

key players in stem cell-derived cells market are focused on generating high-end quality cardiomyocytes as well as hepatocytes that enables end use facilities to easily obtain ready-made iPSC-derived cells. As the stem cell-derived cells market registers a robust growth due to rapid adoption in stem cellderived cells therapy products, there is a relative need for regulatory guidelines that need to be maintained to assist designing of scientifically comprehensive preclinical studies. The stem cell-derived cells obtained from human induced pluripotent stem cells (iPS) are initially dissociated into a single-cell suspension and later frozen in vials. The commercially available stem cell-derived cell kits contain a vial of stem cell-derived cells, a bottle of thawing base and culture base.

The increasing approval for new stem cell-derived cells by the FDA across the globe is projected to propel stem cell-derived cells market revenue growth over the forecast years. With low entry barriers, a rise in number of companies has been registered that specializes in offering high end quality human tissue for research purpose to obtain human induced pluripotent stem cells (iPS) derived cells. The increase in product commercialization activities for stem cell-derived cells by leading manufacturers such as Takara Bio Inc. With the increasing rise in development of stem cell based therapies, the number of stem cell-derived cells under development or due for FDA approval is anticipated to increase, thereby estimating to be the most prominent factor driving the growth of stem cell-derived cells market. However, high costs associated with the development of stem cell-derived cells using complete culture systems is restraining the revenue growth in stem cell-derived cells market.

The global Stem cell-derived cells market is segmented on basis of product type, material type, application type, end user and geographic region:

Segmentation by Product Type

Segmentation by End User

The stem cell-derived cells market is categorized based on product type and end user. Based on product type, the stem cell-derived cells are classified into two major types stem cell-derived cell kits and accessories. Among these stem cell-derived cell kits, stem cell-derived hepatocytes kits are the most preferred stem cell-derived cells product type. On the basis of product type, stem cell-derived cardiomyocytes kits segment is projected to expand its growth at a significant CAGR over the forecast years on the account of more demand from the end use segments. However, the stem cell-derived definitive endoderm cell kits segment is projected to remain the second most lucrative revenue share segment in stem cell-derived cells market. Biotechnology and pharmaceutical companies followed by research and academic institutions is expected to register substantial revenue growth rate during the forecast period.

North America and Europe cumulatively are projected to remain most lucrative regions and register significant market revenue share in global stem cell-derived cells market due to the increased patient pool in the regions with increasing adoption for stem cell based therapies. The launch of new stem cell-derived cells kits and accessories on FDA approval for the U.S. market allows North America to capture significant revenue share in stem cell-derived cells market. Asian countries due to strong funding in research and development are entirely focused on production of stem cell-derived cells thereby aiding South Asian and East Asian countries to grow at a robust CAGR over the forecast period.

Some of the major key manufacturers involved in global stem cell-derived cells market are Takara Bio Inc., Viacyte, Inc. and others.

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The market report addresses the following queries related to the Stem Cell-Derived Cells market:

The study objectives of Stem Cell-Derived Cells Market Report are:

To analyze and research the Stem Cell-Derived Cells market status and future forecast in United States, European Union and China, involving sales, value (revenue), growth rate (CAGR), market share, historical and forecast.

To present the Stem Cell-Derived Cells manufacturers, presenting the sales, revenue, market share, and recent development for key players.

To split the breakdown data by regions, type, companies and applications

To analyze the global and key regions Stem Cell-Derived Cells market potential and advantage, opportunity and challenge, restraints and risks.

To identify significant trends, drivers, influence factors in global and regions

To analyze competitive developments such as expansions, agreements, new product launches, and acquisitions in the Stem Cell-Derived Cells market.

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Stem Cell-Derived Cells Market Forecasted To Surpass The Value Of US$ XX Mn/Bn By 2019 - 2029 - Stock Market Funda

Ghosh Addresses Brentuximab Vedotin Use in Advanced Hodgkin Lymphoma – Targeted Oncology

Nilanjan Ghosh, MD, PhD, a medical oncologist at Levine Cancer Institute, Atrium Health in Charlotte, NC, discussed the case of a 22-year-old patients with advanced Hodgkin lymphoma.

Targeted Oncology: What is your assessment of the patient?

GHOSH: The patients serum albumin is 4.2 g/dL, so thats an issue. The fact that she has stage IV disease, and that the white cell count was high, and the lymphocyte count was low are factors leading to an International Prognostic Score [IPS] of 4. The 5-year overall survival for high IPS, based on historical data, is not as good. I dont know if this would apply as much now, but this is what we have if we use the historical data. That suggests that she is a higher-risk patient. To be honest, the IPS has not affected treatment choice as much, at least in the United States, but well see if some of the newer treatments such as brentuximab vedotin [Adcetris] plus doxorubicin/vinblastine/dacarbazine [A+AVD] have any effect on that subgroup.

What do the National Comprehensive Cancer Network guidelines recommend for stage III or IV disease?

There are 2 treatment pathways that can be followed in patients who have stage III or IV.1 One focuses on a PET-adaptive pathway, which is ABVD [adriamycin, bleomycin, vinblastine, dacarbazine], followed by AVD [adriamycin, vinblastine, dacarbazine] or BEACOPP [bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone]. The non-PET adaptive therapy is the other pathway and uses brentuximab vedotin and AVD or escalated BEACOPP. Escalated BEACOPP is not usually used in North America.

Which regimen was chosen in this patient?

The patient was treated with brentuximab vedotin and AVD. Interim PET scan shows a Deauville score of 3; the patient tolerated this regimen well with G-CSF support. I think most people are certainly familiar with the Deauville scoring system, so just remembering that if the uptake is less than the liver, that is considered as grade 3 response. If its uptake is moderately above or markedly above, then thats considered progressive.

What are the key findings of the ECHELON-1 study (NCT01712490)2?

ECHELON-1 evaluated brentuximab and AVD versus ABVD. The standard of care is ABVD. The most important thing to note is the dose of brentuximab, which is 1.2 mg/kg, not 1.8 mg/kg, because this is given every 2 weeks. Its mirroring when ABVD is administered.

[This was a] large study with [more than] 1200 patients. It examined patients with stage III or IV classical Hodgkin lymphoma who had relatively good performance status. The investigators did allow patients to enroll if they had measurable disease and adequate liver and renal function. There was a PET scan at the end of cycle 2; however, this was not a PET-adaptive therapy. ABVD was given for 6 cycles. There is no decrease to AVD or escalation to BEACOPP

At 3 years, the progression-free survival [PFS] rate was 83% in the treatment arm and 76% in the control arm. This is highly significant, with a P value of .005, a hazard ratio of 0.7.

Overall, subgroup analysis favors brentuximab and AVD. But the confidence intervals do cross over in some categories, especially in the regional subgroup. For some reason, ABVD seems to do better in Asia. The study, though, is not powered to determine if 1 region is better than another. So, you have to take this kind of data with a grain of salt.

Now, remember this patient was young; shes in her early 20s. In a younger age group, the A+AVD did better than ABVD. She lives in North America, so thats a region where ABVD did better. And then looking at the IPS, she had a score of 4, and thats another group in which A+AVD did better.

In general, A+AVD would probably be favored in stage IV disease. Her symptoms are associated with having extranodal sites, and in our case, the patients extranodal site was associated with the bones. Her performance status is good.

Looking at the responses in ECHELON-1, the overall response rate was 86% versus 83%, so there are small differences.

Regarding adverse effects [AEs], remember that when we think about brentuximab, we think of peripheral neuropathy. In the study, peripheral neuropathy was 67% for the treatment arm versus 42% in the ABVD arm. For diarrhea, its 27% versus 18%, and abdominal pain was slightly higher in ABVD, as well. In terms of any AEs, theyre similar; grade 3 events were more for A+AVD versus ABVD.

I will mention that initially in the protocol there was no mandate for growth factor, so most patients were treated without growth factors. There were increasing incidences of neutropenia and neutropenic fevers in the A+AVD arm. Protocol amendments were performed later and G-CSF support was introduced. It was the middle part of the program. The guidelines recommend that A+AVD should be used with G-CSF support. But the protocol for the most part didnt initiate G-CSF support except toward the end. So, we see 83 patients who [received] G-CSF support and 579 who didnt.

In terms of serious AEs, there were more associated with A+AVD. The reason I bring that up is because the majority of that protocol was already carried out without the G-CSF support. The treatment group ended up seeing more AEs and clearly there are more incidences of neuropathy with A+AVD. Drug discontinuation, however, was about the same between the groups. Deaths during treatment [were] very low, and there were more hospitalizations observed with A+AVD.

Did investigators initiate any dose delays?

Most of the dose delays were initiated because of neutropenia and febrile neutropenia. For patients who discontinued more than 1 drug because of AEs, 7% were attributed to peripheral neuropathy, which is an important AE in this treatment.

Regarding pulmonary toxicity, we would expect a bleomycin-containing regimen would have higher pulmonary toxicity. It was seen in 7% of patients with ABVD and 2% with A+AVD,

and grade 3 or more pulmonary toxicity was low in A+AVD but observed in 3% of patients with ABVD.2

How were febrile neutropenia and any neutropenia addressed in the trial?

We see a difference between patients who [received] G-CSF support versus those who didnt, regarding febrile neutropenia versus any neutropenia. In patients who developed febrile neutropenia during treatment, 11% of those who received G-CSF support experienced the AE, and 21% who did not receive G-CSF support experienced the AE.

For neutropenia any grade, 73% of patients who did not receive GCSF versus 35% of patients who did receive G-CSF support developed it. Similarly, for grade 3 or more neutropenia, 70% who did not receive G-CSF versus 29% of patients who did developed it. To me, that is the most striking observation.

In the ABVD arm, there was neutropenia observed with ABVD, and we all have had patients with ABVD where the absolute neutrophil count is low, and we still go ahead and treat. That is done in standard practice.

In terms of serious AEs, there were more serious AEs with A+AVD compared [with] ABVD, 44% versus 28%. And there were no differences in deaths.

The A+AVD regimen can cause peripheral neuropathy. But if you look at complete resolution of peripheral neuropathy, you can see that 78% of patients treated with A+AVD had complete resolution and 83% of those on ABVD had complete resolution. Patients receiving ABVD also get neuropathy primarily because of vinblastine. Improvement in neuropathy also occurred in both groups; 17% of patients had improvement, not resolution, in the A+AVD arm versus 9% in the ABVD arm. The vast majority had resolution, but many had improvement as well.

However, for ongoing neuropathy that [was] grade 1 or 2, 25% of patients in the A+AVD arm and only 11% in the ABVD group experienced this. We have to be vigilant and monitor them throughout treatment so that it doesnt get too bad, so appropriate dose reductions can be made.

The bottom line here is most neuropathy is going to go away, but there will be patients where neuropathy can persist, and that can be an annoying thing, especially for a young person. For many in long-term follow-up, theyll experience improvement in neuropathy over time, which means things are getting better, but that doesnt mean its all resolved.

References:

1. NCCN Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 2.2020. Accessed August 26, 2020. http://bit.ly/2YAIYha

2. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkins lymphoma. N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984

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Ghosh Addresses Brentuximab Vedotin Use in Advanced Hodgkin Lymphoma - Targeted Oncology

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