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Archive for the ‘IPS Cell Therapy’ Category

Abu Dhabi Stem Cells Centre partners with Rege Nephro and Kyoto University’s Center for iPS Cell Research and … – Abu Dhabi Media Office

Abu Dhabi Stem Cells Centre partners with Rege Nephro and Kyoto University's Center for iPS Cell Research and ...  Abu Dhabi Media Office

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Abu Dhabi Stem Cells Centre partners with Rege Nephro and Kyoto University's Center for iPS Cell Research and ... - Abu Dhabi Media Office

Abu Dhabi Stem Cells Center partners with Japan-based Kyoto University and Rege Nephro – ZAWYA

Abu Dhabi Stem Cells Center partners with Japan-based Kyoto University and Rege Nephro  ZAWYA

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Abu Dhabi Stem Cells Center partners with Japan-based Kyoto University and Rege Nephro - ZAWYA

Shinobi Therapeutics Launches with Completion of $51M Series A to Advance Hypoimmune iPS-T Cell Therapy Platform – PR Newswire

Shinobi Therapeutics Launches with Completion of $51M Series A to Advance Hypoimmune iPS-T Cell Therapy Platform  PR Newswire

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Shinobi Therapeutics Launches with Completion of $51M Series A to Advance Hypoimmune iPS-T Cell Therapy Platform - PR Newswire

Eterna Therapeutics Enters Into Option and License Agreement with Lineage Cell Therapeutics to Develop Hypoimmune Pluripotent Cell Lines for Multiple…

Eterna Therapeutics Enters Into Option and License Agreement with Lineage Cell Therapeutics to Develop Hypoimmune Pluripotent Cell Lines for Multiple Neurology Indications  Marketscreener.com

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Eterna Therapeutics Enters Into Option and License Agreement with Lineage Cell Therapeutics to Develop Hypoimmune Pluripotent Cell Lines for Multiple...

Cell Therapy – an overview | ScienceDirect Topics

Stem Cell Therapy

Cell therapy involves the direct administration of cells into the body for healing purposes. The units of therapy in this approach are single cells. For regenerative medicine, the ultimate objective of cell therapy is to establish a long-term graft with the capacity to perform organ functions. A practical example is bone marrow transplantation, in which HSC are the units of therapy, engraft in the bone marrow, and repopulate the entire blood lineage.105

Intravenous administration describes the direct injection of dissociated cells into the bloodstream using a syringe. It is the simplest delivery route for cell therapies and is used for HSC therapy in the clinic. Kidney cells, however, are different from blood cells and do not typically circulate throughout the body. The kidney is furthermore a densely-packed organ with no obvious route for stem cells to traverse from the bloodstream into the nephrons. Whether kidney stem cells have the ability to engraft and regenerate the kidney after intravenous administration therefore needs to be tested in preclinical animal models. In these experiments, the kidneys are typically subjected to acute injury. This damages the glomerular filtration barrier, which can enhance penetration of cells into the kidney and subsequent engraftment.

In one example, human iPS cell-derived cells expressing a variety of NPC and adult kidney cell markers were injected into the mouse tail vein 24 hours after administration of the nephrotoxic drug cisplatin.106 Extensive engraftment was reported in proximal tubules, which coincided with a 55% reduction in urea levels in treated mice, compared with control animals administered with saline or undifferentiated iPS cells.106 These experiments suggest a possible benefit of iPS-derived kidney cells on kidney injury. However, the isolated cells were not shown to demonstrate the ability to form kidney organoids with segmented nephrons. It is therefore unclear whether the implanted cells contained bona fide NPC or whether new nephrons were actually formed.

Intravenous administration has also been applied to adult kidney cell populations. Human glomerular epithelial transitional cells (see earlier), administered intravenously into a mouse model of chemically-induced podocytopathy, were found in glomeruli, and were associated with a decrease in proteinuria.107 These cells also contributed to tubules after acute injury.80 As these cells cannot form new nephrons, this approach seeks to repair and replace, rather than to completely regenerate.

MSC can be readily obtained, for instance from a patient's adipose tissue. Intravenous administration of MSC in experimental models can have a beneficial effect on ischemia-reperfusion injury.99,102,108 This benefit can be obtained even in the absence of MSC engraftment, likely via a paracrine effect. However, MSC administered to injured kidneys do not contribute tangibly to new nephron formation and can differentiate ectopically into undesirable fat cells or fibroblasts within glomeruli.108,109 Collectively, these findings suggest that intravenous administration of cell therapeutics may provide some benefit in cases where the glomerular filtration barrier has been compromised but may also have unwanted side effects.

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Cell Therapy - an overview | ScienceDirect Topics

Stem Cell Therapy for Parkinson’s: Current Developments – Healthline

Parkinsons disease is a neurological disorder with symptoms that become more severe over time. It affects about 1% of people ages 60 years and older in industrialized nations. The exact cause of the disease isnt known, but experts believe that both genetic and environmental factors play a role.

Parkinsons disease causes neurons to die in certain parts of your brain, leading to a decrease of dopamine. Dopamine is a neurotransmitter. Cells in your brain release dopamine as a way of sending signals to other nearby cells.

When you have Parkinsons, a decrease in dopamine activity can lead to such symptoms as:

Theres no cure for Parkinsons disease. But over the past few decades, researchers have been studying stem cell therapy to provide better treatment options.

Read on to learn more about current and future developments in using stem cell therapy to treat Parkinsons disease.

Stem cells are special because theyre undifferentiated, meaning they have the potential to become many types of specialized cells.

You might think of stem cells as natural resources for your body. When your body needs a specific type of cell from bone cells to brain cells an undifferentiated stem cell can transform to fit the need.

There are three main types of stem cells:

Stem cell therapy is the use of stem cells usually from a donor, but sometimes from your own body to treat a disorder.

Because Parkinsons disease leads to the death of brain cells, researchers are trying to use stem cells to replace brain cells in the affected areas. This could help treat the symptoms of Parkinsons disease.

Researchers are exploring various approaches to use stem cells to treat Parkinsons disease.

The current idea is to introduce stem cells directly into the affected areas of your brain where they can transform into brain cells. These new brain cells could then help regulate dopamine levels, which should improve the symptoms of the disease.

Its important to note that experts believe this would only be a treatment for Parkinsons disease and not a cure.

While stem cell therapy has the potential to replace the brain cells destroyed by Parkinsons disease, the disease would still be present. Parkinsons disease would likely destroy the implanted stem cells eventually.

Its unclear right now whether stem cell therapy could be used multiple times to continue to reduce symptoms of Parkinsons disease or if the effect would be the same after multiple procedures.

Until the discovery of the process of creating iPSCs, the only stem cell therapies for Parkinsons disease required the use of embryonic stem cells. This came with ethical and practical challenges, making research more difficult.

After iPSCs became available, stem cells have been used in clinical trials for many conditions involving neural damage with overall mixed results.

The first clinical trial using iPSCs to treat Parkinsons disease was in 2018 in Japan. It was a very small trial with only seven participants. Other trials have been completed using animal models.

So far, trials have shown improvement to symptoms affecting movement as well as nonmotor symptoms such as bladder control.

Some challenges do arise from the source of the stem cells.

Stem cell therapy can be thought of as being similar to an organ transplant. If the iPSCs are derived from a donor, you may need to use immunosuppressant drugs to prevent your body from rejecting the cells.

If the iPSCs are derived from your own cells, your body might be less likely to reject them. But experts believe that this will delay stem cell therapy while the iPSCs are made in a lab. This will probably be more costly than using an established line of tested iPSCs from a donor.

There are many symptoms of Parkinsons disease. Theyre often rated using the Unified Parkinsons Disease Rating Scale (UPDRS) or the Movement Disorder Societys updated revision of that scale, the MDS-UPDRS.

Clinical trials today are generally looking to significantly improve UPDRS or MDS-UPDRS scores for people with Parkinsons disease.

Some trials are testing new delivery methods, such as intravenous infusion or topical applications. Others are looking to determine the safest number of effective doses. And other trials are measuring overall safety while using new medical devices in stem cell therapy.

This is an active area of research. Future trials will help narrow down the most safe and effective approach to stem cell therapy for Parkinsons disease.

Clinical trials are usually conducted in three phases. Each phase adds more participants, with the first phase usually limited to a few dozen people and several thousand in the third phase. The purpose is to test the treatments safety and effectiveness.

Clinical trials testing stem cell therapy for Parkinsons disease are still in the early phases. If the current trials are successful, it will likely still be 4 to 8 years before this treatment is widely available.

The goal of stem cell therapy for Parkinsons disease is to replace destroyed brain cells with healthy, undifferentiated stem cells. These stem cells can then transform into brain cells and help regulate your dopamine levels. Experts believe this can relieve many of the symptoms of Parkinsons disease.

This therapy is still in the early stages of clinical testing. Many trials are either proposed, currently recruiting, or already active. The results of these trials will determine how soon stem cell therapy might become widely available as a treatment for Parkinsons disease.

At the moment, its not believed that stem cell therapy will cure Parkinsons disease. But it might be an alternative to existing treatments such as drug therapies and deep brain stimulation.

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Stem Cell Therapy for Parkinson's: Current Developments - Healthline

Cell and Gene Therapy World Asia Event – IMAPAC

Since 2017, Cell & Gene Therapy World Asia haswitnessed huge success in bringing over 300industry pioneers from both cell & gene therapyindustry. With the mission to facilitate the research& development and manufacturing of high qualitycell & gene therapy treatments and regenerativemedicines in Asia, Cell & Gene Therapy World Asia isgoing to continue its legacy.

In addition, this year, speakers will be exploringinnovations in cell & gene therapy in Asia region,best practices on cell & gene therapymanufacturing and process development, scale outstrategies, cost optimization, next generation onCART, advances in CART manufacturing,preparation for commercialization, regulation casestudies and more.

Join the conference to interact with key andupcoming entities from Asia cell & gene therapycompanies including BeiGene, GracellBiotechnologies, Fosun Kite Biotechnology, TessaTherapeutics, CARSgen, Senlang Bio, KangstemBiotech, Medigen Biotechnology Corp, ShangaiUniCAR Therapy among others.

Catch the latest cell & gene therapy development inAsia. From current best R&D practices to advancingtowards manufacturing and commercializationfrom most-exclusive case studies to industry's keyneeds. All this and more under 1 roof.

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Cell and Gene Therapy World Asia Event - IMAPAC

Present and Future Perspectives on Cell Sheet-Based … – Hindawi

Heart failure is a life-threatening disorder worldwide and many papers reported about myocardial regeneration through surgical method induced by LVAD, cellular cardiomyoplasty (cell injection), tissue cardiomyoplasty (bioengineered cardiac graft implantation), in situ engineering (scaffold implantation), and LV restrictive devices. Some of these innovated technologies have been introduced to clinical settings. Especially, cell sheet technology has been developed and has already been introduced to clinical situation. As the first step in development of cell sheet, neonatal cardiomyocyte sheets were established and these sheets showed electrical and histological homogeneous heart-like tissue with contractile ability in vitro and worked as functional heart muscle which has electrical communication with recipient myocardium in small animal heart failure model. Next, as a preclinical study, noncontractile myoblast sheets have been established and these sheets have proved to secrete multiple cytokines such as HGF or VEGF in vitro study. Moreover, in vivo studies using large and small animal heart failure model have been done and myoblast sheets could improve diastolic and systolic performance by cytokine paracrine effect such as angiogenesis, antifibrosis, and stem cell migration. Recently evidenced by these preclinical results, clinical trials using autologous myoblast sheets have been started in ICM and DCM patients and some patients showed LV reverse remodelling, improved symptoms, and exercise tolerance. Recent works demonstrated that iPS cell-derived cardiomyocyte sheet were developed and showed electrical and microstructural homogeneity of heart tissue in vitro, leading to the establishment of proof of concept in small and large animal heart failure model.

Therapeutic treatments using cells or cell-based tissues have been developed to regenerate the damaged myocardium associated with ischemic heart disease. This technique has already been evaluated in the clinical setting, using myoblasts [1] or bone marrow mononuclear cells (BM-MNCs) [2]. Although these studies demonstrated the feasibility and safety of this approach, the efficacy associated with this technology was generally insufficient to repair severe myocardial damage. Thus, a second generation of myocardial regenerative therapy, tissue-engineered cardiomyoplasty, is currently being developed. A large number of achievements concerning basic, preclinical, and clinical works about cell sheet technology have been done and this review summarizes recent advances in myocardial regeneration emerging from the development of cell sheet technology.

Cell-sheet techniques have been applied to several diseased organs, such as the heart [3], eye [4], and kidney [5], in the laboratory and the clinic. Cell sheets can be prepared on special dishes that are coated with a temperature-responsive polymer, poly(N-isopropylacrylamide) (PIPAAm), that changes from being hydrophobic to hydrophilic when the temperature is lowered. This change allows cells to be removed without EDTA or enzymatic treatment and without destroying the cell-cell or cell-extracellular matrix (ECM) interactions within the cell sheet.

Shimizu et al. used such temperature-sensitive culture dishes to develop a contractile chick cardiomyocyte sheet that exhibited a recognizable heart tissue-like structure and showed electrical pulsatile amplitude [6]. Next, they layered single-cell sheets to generate bilayer-cell sheets, forming an electrically communicative three-dimensional cardiac construct, which exhibited spontaneous and synchronous pulsation with electrical communication between the cell sheets, mediated by connexin 43. Furthermore, the cell sheets adhered together rapidly, as indicated by the presence of desmosomes and intercalated disks between them [7]. When the pulsatile cardiac tissue was implanted subcutaneously, it was found to assume a heart tissue-like structure and exhibited neovascularization and spontaneous beating for up to one year. The size, conduction velocity, and contractile force of the engrafted sheets increased in proportion to the host growth [8, 9].

Miyagawa et al. demonstrated that a neonatal cardiomyocyte sheet could communicate electrically with the host myocardium, as indicated by the presence of connexin 43, and changes in the QRS wave and action potential amplitude, leading to improved cardiac performance in a rat model of ischemic heart disease [3]. This study clearly showed electrical and morphological coupling between the cell sheet and host myocardium and that the cell sheet could contract synchronously with the beating of the host heart and improve the regional systolic function.

A detailed analysis of the vascularization process following cell sheet implantation was undertaken by Sekiya et al. These authors reported that the cardiomyocyte sheet expresses angiogenesis-associated genes and forms an endothelial cell network. Evidence was also presented suggesting that the vessels arising in the engrafted sheet migrate to connect with the host vasculature [10].

Myocardial tissue grafts engineered with cell sheet technology represent a promising therapy for repairing the damaged myocardium, but there may be some inherent limitations. For example, cellular treatment for heart failure may be not suitable for emergency situations. Another issue is that wide therapeutic use will require improvement in the uniformity in the quality of the cultured cells.

Recently, new medications that imitate the paracrine effects of cytokines in cell sheets have been reported, and the addition of such medications could improve the regenerative treatment for heart failure. It was reported that the direct introduction of a prostacyclin agonist into the damaged myocardium induced significant functional recovery in a canine model of dilated cardiomyopathy, via the upregulation of multiple cytokines, including HGF, VEGF, and SDF-1 [11]. Similarly, the implantation of an atelocollagen sheet containing a prostacyclin analogue induced improved cardiac function and a prolonged survival rate in a mouse model of acute myocardial infarction, accompanied by an enhanced expression of SDF-1 [12]. Recent work has also revealed that prostacyclin may be upregulated in the implanted myoblast sheet in the early phases after implantation in response to ischemic conditions and may in turn stimulate endothelial or smooth muscle cells to secrete multiple cytokines including HGF, VEGF, and SDF-1 (data not shown).

In the clinical setting, cellular cardiomyoplasty is reported to have potential regenerative capability, and a method using skeletal myoblasts has been evaluated in clinical trials and found to be relatively feasible and safe [13]. For tissue cardiomyoplasty, skeletal myoblasts are the cell source closest to being ready for clinical application at this time. Memon et al. demonstrated that the nonligature implantation of a skeletal myoblast sheet into a rat cardiac ligation model regenerated the damaged myocardium and improved global cardiac function, by attenuating cardiac remodeling via hematopoietic stem-cell recruitment and growth-factor release, with better restoration of the implanted cells than that obtained using needle injection [14]. In another study, the application of a skeletal myoblast sheet into a 27-week dilated cardiomyopathy hamster model resulted in the attenuated deterioration of cardiac performance accompanied by the preservation of alpha-sarcoglycan and beta-sarcoglycan expression in the host myocytes, and an inhibition of fibrosis, leading to prolonged survival rates [15]. In addition, the grafting of skeletal myoblast sheets attenuated cardiac remodeling and improved cardiac performance in a pacing-induced canine heart failure model [16]. Studies from our group have shown that myoblast sheets may improve cardiac performance via cytokines such as HGF or VEGF (XX).

The mechanism of recovery in the damaged myocardium has not been completely elucidated and may be very complicated. As mentioned above, cytokine release and hematopoietic stem-cell recruitment are possible mechanisms of regeneration; however, other regenerative mechanisms are likely to be involved as well. Skeletal myoblasts cannot beat synchronously with the host myocardium in vitro [17] or in vivo [18], and, thus, they do not appear to be functionally integrated. However, data from our human and porcine studies suggested that after myoblast sheet implantation, the diastolic dysfunction in the distressed region of the myocardium was significantly recovered compared with controls, leading to improved systolic function in the same region, without contraction of the implanted myoblasts (data not shown). Massive angiogenesis in the implanted region was detected histologically and appeared to be a critical feature associated with the improvement. Thus, we speculate that angiogenesis and the recovery of diastolic function are both major components of the regenerative mechanism in myoblast sheet implantation [19].

On the other hand, immunohistochemical analysis has indicated that the myoblast sheet may only survive for a few months after implantation. We speculate that in the early phases after implantation of the myoblast sheet, the ischemic conditions induce the upregulated expression of several cytokines by the myoblasts that promote their own survival. These cytokines then in turn enhance angiogenesis and the recruitment of stem cells, leading to improved blood perfusion to reactivate the damaged myocardium. The system may continue to be effective in spite of the short-lived myoblast sheet, due to long-term maintenance of the newly developed vasculature.

We recently initiated a clinical evaluation of autologous myoblast sheet implantation. We tested the technology in four patients who were using left ventricular assist devises (LVADs); three of the four patients showed functional recovery, and in two of the patients, the treatment provided a bridge to recovery [20]. Six years later, these two patients have no symptoms of heart failure. We have also implanted myoblast sheets into eight patients with ischemic cardiomyopathy and seven with dilated cardiomyopathy (who were not using LVADs). In that study, some of the patients exhibited left ventricle reverse remodeling and improvements in exercise tolerance and symptoms, with no major adverse cardiac events (MACEs) (data not shown). This clinical research program is ongoing, as we continue to evaluate patients with dilated cardiomyopathy and ischemic cardiomyopathy with and without the use of LVADs.

In addition to cardiomyocytes and myoblasts, other types of cell sheets have been used effectively to improve cardiac performance. The transplantation of a mesenchymal stem cell (MSC) sheet onto the infarcted myocardium of rats resulted in increased anterior wall thickness and new vessel formation, accompanied by a low incidence of differentiation of the implanted cells to cardiomyocytes [21]. While the small number of differentiated cardiomyocytes may not have contributed to the observed improvement in systolic function in this study, the cell sheet exhibited self-propagating properties that promoted the generation of a thick-layered sheet. Although the MSC sheet exhibited a maximum thickness of approximately 600m, which would not be strong enough to correct human end-stage heart failure [22], this method of self-propagation is a potential strategy for creating a thick-layered sheet in vivo, with the potential for cardiac tissue regeneration.

A further development in cell sheet technology is the creation of a cell sheet composed of two types of cocultured cells; this type of cell sheet was developed to enhance angiogenesis [23, 24]. The cocultured cell sheet, which combined fibroblasts and endothelial progenitor cells, enhanced blood vessel formation and led to functional improvement in a rat myocardial infarction model [24]. Cocultured cell sheets combining fibroblasts and human smooth muscle cells were found to accelerate the secretion of angiogenic factors in vitro and to increase blood perfusion in vivo by the formation of new vessels [25]. This enhanced effectiveness attained by coculturing two cell types is supported by another study in which the coimplantation of BMCs and myoblasts showed improved results compared to the transplantation of a single cell type in a canine model of ischemic cardiomyopathy [26].

Cell sheets composed of stem cell antigen-1- (sca-1-) positive, or kit-positive cells may represent additional promising approaches. Matsuura et al. demonstrated that sca-1-positive cell sheets could differentiate into cardiomyocytes in vivo and produce VCAM-1, leading to improved cardiac performance in a mouse model of myocardial infarction [27]. The administration of c-kit-positive stem cells has shown efficacy in animal models of cardiac dysfunction, and this approach is currently being tested in clinical trials in combination with coronary artery bypass grafting, with encouraging preliminary results [28]. In another study, a c-kit-positive cell sheet combined with endothelial progenitor cell injection was found to induce better functional recovery of endocardial scar tissue than that induced by the cell sheet alone, despite the poor transdifferentiation ability of the c-kit-positive cells into cardiomyocytes [29].

Many of the cell sources mentioned above demonstrate regenerative ability based on the paracrine effect of secreted cytokines; however, newly differentiated cardiomyocytes may be the best candidate cells to regenerate the damaged myocardium. In 2006, Takahashi and Yamanaka reported the development of induced pluripotent stem (iPS) cells that can differentiate into various types of cells, such as cardiomyocytes, cartilage, and nerve cells [30]. Since then, there have been many reports showing that cardiomyocytes derived from iPS cells demonstrate electrophysiological, functional, and microstructural similarities to native cardiomyocytes [31]. Cardiomyocyte sheets derived from human or mouse iPS cells that contract synchronously in vitro have been developed, and studies indicate that these cardiomyocyte sheets can contract in vivo as analyzed by X-ray diffraction with synchrotron radiation. The transplantation of these sheets leads to functional recovery with upregulated electrical potential in the scarred areas in large [32] and small animal myocardial infarction models [33].

Although preclinical studies appear promising, the safety of these artificially generated cells must be evaluated thoroughly before they can be used in the clinic. In addition, a potential limitation of iPS cell-derived cardiomyocytes may be the loss of cardiomyocytes due to ischemia after implantation. Recent studies have proposed supplemental strategies to avoid ischemia. In one study, the combination of an iPS-derived cardiomyocyte sheet with omentum, which has a rich vasculature network, resulted in retention of the implanted cardiomyocytes and enhanced functional recovery compared with the cardiomyocyte sheet alone [34]. In another study, the transplantation of a cardiomyocyte sheet containing iPS cell-derived endothelial cells led to enhanced functional recovery in a rat myocardial infarction model and increased survival of the implanted cardiomyocytes [35]. Thus, to successfully treat the severely damaged myocardium using iPS cell-derived cardiomyocyte sheets, additional strategies to increase angiogenesis and reduce ischemia may be required.

Studies on the original myoblast cell therapy, in which cells were directly injected into the myocardium, indicated that the proportion of injected cells surviving to engraft the infarcted myocardium was too low to be effective. This low level of engraftment may have been caused by the injected cells leaking out of the injected region and being carried to other organs, or due to mechanical stress resulting in cellular loss of function. The resulting rapid cell loss [14] limited the usefulness of the original myoblast cell therapy.

To overcome the problems associated with the intramyocardial injection of cells, many investigators have combined cell transplantation with protein or gene therapy [36], or with tissue-engineered techniques [3]. We have also developed a new cell delivery system that uses tissue-engineered myoblast grafts grown as cell sheets and have utilized animal studies to guide clinical trials. These studies showed that the viability of the transplanted cells was higher than that of injected cells, and that the transplanted myoblasts survived for at least 3 months in the cardiac tissue of a porcine model of heart failure treated with autologous myoblast sheets. Using tissue-engineered temperature responsive techniques, we found that the implanted cells could be applied in larger numbers, were viable during transplantation, and were not lost from the applied region. Furthermore, we showed that cell sheets could be engrafted onto the failed myocardium and contribute to the attenuation of cardiac dysfunction and remodeling [14].

In cell therapy for cardiac disease, life-threatening adverse events involving arrhythmogenicity are a potential risk in both animal models and human clinical trials [37]; however, life-threatening arrhythmias have not been observed during the clinical course of patients who have received autologous cell sheet transplants. In any case, arrhythmias can occur during the natural clinical course of severe heart failure, so their cause may not be easily determined. Procedures using needle injection may cause scars in the myocardium that could in turn induce arrhythmias. Our cell delivery techniques using cell sheets prepared on temperature-responsive culture dishes may carry less risk for the induction of arrhythmias. Myoblasts have a weak electrical potential, and it may be possible for these cells to induce arrhythmia if they survive in the myocardium. However, cell sheets may not be able to induce arrhythmia, since they are attached to the epicardium.

Another potential problem is the limited blood perfusion to the implanted cell sheets. Although the survival of implanted cells using the cell sheet technique has already been shown to exceed the cell survival using other delivery routes, the survival rate was still found to be relatively low when the cells were implanted on the epicardium with this technique [38]. Although we have reported that improved cardiac performance depends on the dose of implanted myoblast sheets, the use of too many cell sheets results in a reduced blood supply. Thus, additional strategies, such as combining myoblasts with angiogenic factors [36] or other types of cells [23] to establish a vasculature network, may be needed to solve this problem. One strategy discussed above, is the combination of a myoblast sheet with omentum tissue that has a rich vasculature network. One report recently demonstrated the effectiveness of this approach for retention of the implanted cell sheets [39]. This report also suggested that the implanted myoblast sheet might induce vasculature connections between arteries of the transplanted omentum and the native coronary arteries, suggesting the possibility of biocoronary artery bypass grafting. This method may also be used in conjunction with iPS cell-derived cardiomyocytes to generate an artificial thick cardiac structure with increased vascular connections.

In this review, we surveyed many exciting topics in the area of cell sheet technology for cardiac repair. Owing to these studies, some techniques have already been tested in clinical applications, but the mechanisms by which they improve cardiac function are only partially understood, and much of the technology is still in the early stages of development, both experimentally and in the clinic. Nevertheless, the field of clinical myocardial regenerative therapy holds much promise, and we expect to witness more progress in this innovative technology in the near future.

The authors declare that there is no conflict of interests regarding the publication of this paper.

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Present and Future Perspectives on Cell Sheet-Based ... - Hindawi

Stem cell therapy side effects & risks: infections, tumors & more

What are the possible stem cell therapy side effects of going to an unproven clinic? This is a common question I get asked. Most often it is asked by patients who reach out.

Check out the YouTube video below on our stem cell channel. If you like such videos please subscribe to our channel.

Many clinics have said over the years to potential customers that the worst that can happen is that the stem cells wont work.

We know this isnt true and its irresponsible.

Anything that has the potential to help a medical condition also poses some risks of harm. For this reason, its important to discuss potential stem cell therapy side effects. In this case I am focusing on the risks primarily associated with unproven stem cell clinics. Not for established methods like bone marrow transplantation.

Recent publications in journals including one by my colleague Gerhard Bauer and a special report by The Pew Charitable Trust have helped clarify risks. Gerhards paper presents the types of side effects that appear more common after people go to stem cell clinics. After closely following this area for a decade I was familiar with many of the examples of problems. However, some were new to me.

One of the highest profiles examples of bad outcomes was the case where three people lost their vision due to stem cells injected by a clinic.See image below of one set of damaged eyes. More on that case at the end of the post.

Why do stem cells pose risks?

Stem cells are uniquely powerful cells.

By definition they can both make more of themselves and turn into at least one other kind of specialized cells. This latter process is called differentiation. That former ability to make more of themselves is called self-renewal.

The most powerful stem cells are totipotent stem cells that can literally make any kind of differentiated cell. The fertilized human egg is the best example of a cell having totipotency. Next in the power line are pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Adult stem cells are multipotent. The best type of stem cell depends on the condition that is trying to be treated. The best type may not be the most powerful.

In any case, the power of stem cells is a main reason they also pose risks. These cells are not always easy to control and misdirected power can do harm.

Let me explain and start with the side effect that seems scariest to most.

If someone injects a patient with stem cells, its possible that the self-renewal power of stem cells just wont get shut off. In that scenario the stem cells could drive formation of a tumor or even cancer. Note that tumors are not always malignant whereas cancer is always malignant.

Why wouldnt a transplanted stem cell always eventually hit the brakes on self-renewal? It could be that the stem cell has one or more mutations. For any stem cells grown in a lab, within the population of millions of cells in a dish, there are going to be at least a few with mutations that crop up. Thats just the way it goes with growing cells in a lab.

Even stem cells not grown in the lab have the same spectrum of mutations as the person they were isolated from. It may seem weird to think about, but we all have some mutations.

When someone like a clinic person tells us that theres a risk to you thats a one in a million chance it doesnt sound that bad. However, with cells being injected into a person in theory all it takes is one cell out of a million cells in a syringe with a couple really bad mutations to potentially cause disaster. Research suggests it takes more than one cell with cancer-causing potential to make a tumor in experiments in the lab, but in actual people we just dont know. Many cancers may arise from one stem cell gone awry. If a clinic injects 50 or 100 million cells, a one-in-a-million rate of dangerous cells means that 50-100 such cells end up in the patient.

The odds are far lower for cells never grown in a lab to cause a tumor, but its still possible. Oddly, its possible that receiving someone elses stem cells (we call this allogeneic) might pose a lower cancer risk because your immune system is going to see those cells as foreign from the start.

But some stem cells, especially those with mutations, might be able to somewhat fly under the radar of the immune system to some extent even if they are from another person. This could allow them to grow into a tumor. The Pew report does a nice job of summarizing risks and there are several reports of tumors.

The possibility of infections after stem cell injections is another risk that is often discussed. Infections from injections of stem cells or other materials like PRP are probably the most common type of side effect. Bacteria can either sometimes already be in the product that is injected or can be introduced by poor injection or preparation methods by the one doing the procedure.

The distributor Liveyon had a product contaminated with bacteria that sickened at least a dozen people who were hospitalized. Some of them ended up in the ICU. A few may even have permanent issues.

Clinics using excellent procedures and products should have a low risk of infection more similar to getting any kind of invasive procedure even unrelated to stem cells.

Many preparations of stem cells sold at stem cell clinics these days are made from fat tissue or birth-related materials. I put stem cells in quotes because most fat and birth-related preparations only contain a small population of true stem cells.

In the case of adipose biologics, they mostly consist of a mixture of a dozen or so other kinds of cells found in fat.

The injections of fat cells are most often made IV right into the bloodstream. Fat cells just live in fat so they arent supposed to be floating around in your blood. As a result, after IV injection, many fat cells are thought to get killed right away.

Others end up landing in the lungs, where many are also probably meeting their doom. However, during this process of wiping out the fat cells it is possible that clots can start forming. Maybe the fat cells form small clots in the blood before they even get into the lungs. Either way, if the clots grow and are big enough, patients can get pulmonary emboli.

The same kind of risk may apply to IV injections or nebulizer inhalations of other kinds of stem cells.

There are other possible risks to stem cell injections too.

I wrote a post about possible graft versus host disease in stem cell recipients. This would only happen in people receiving someone elses stem cells. Its not clear if GvHD is something that happens to patients after going to clinics.

Beyond outright tumor formation it is also possible that stem cells will turn into an undesired or even dangerous tissue type. The example that comes to mind is the practice mentioned earlier of some clinics injecting fat cells into peoples eyeballs. What seems to have happened in some cases is that the mesenchymal cells (MSCs) that were injected turned into scar tissue, which caused retinal detachment. Unfortunately, what are called MSCs by some clinics can mostly consist of close relatives of fibroblasts or in some cases may even largely consist of fibroblasts. Fibroblasts are good at making scar tissue under some circumstances and that can create pull on surrounding tissues including the retina if inside the body.

Specific kinds of stem cells or routes of administration may pose unique risks as well. For instance, intranasal administration of stem cells is getting popular with unproven clinics and could lead to stem cells ending up in the brain.

Other products in the regenerative sphere that are not stem cells may be risky as well for various reasons. For instance, an exosome product harmed quite a few people in Nebraska.Some problems may relate to product contamination.

There have also been cases of unusual immune reactions to stem cell injections.

Finally, stem cells also pose unknown risks because of their power. We just dont have long-term follow up data to have a clear sense of risks.

Related Posts

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Stem cell therapy side effects & risks: infections, tumors & more

Ethical issues in stem cell research and therapy

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Stem cell therapy for diabetes – PMC – PubMed Central (PMC)

Stem cell therapy holds immense promise for the treatment of patients with diabetes mellitus. Research on the ability of human embryonic stem cells to differentiate into islet cells has defined the developmental stages and transcription factors involved in this process. However, the clinical applications of human embryonic stem cells are limited by ethical concerns, as well as the potential for teratoma formation. As a consequence, alternative forms of stem cell therapies, such as induced pluripotent stem cells, umbilical cord stem cells and bone marrow-derived mesenchymal stem cells, have become an area of intense study. Recent advances in stem cell therapy may turn this into a realistic treatment for diabetes in the near future.

Keywords: Embryonic stem cell, induced pluripotent stem cell, mesenchymal stem cell, diabetes

This lecture is based on a recent review.[1]

The increasing burden of diabetes worldwide is well-known, and the effects on health care costs and in human suffering, morbidity, and mortality will be primarily felt in the developing nations including India, China, and countries in Africa. New drugs are being developed at a rapid pace, and the last few years have seen several new classes of compounds for the treatment of diabetes e.g. glucagon-like peptide (GLP-1) mimetics, dipeptidyl-peptidase-4 (DPP-4) inhibitors, sodium glucose transporter-2 (SGLT2) inhibitors. New surgical treatments have also become increasingly available and advocated as effective therapies for diabetes. Gastric restriction surgery, gastric bypass surgery, simultaneous pancreas-kidney transplantation, pancreatic and islet transplantation have all been introduced in recent years. To avoid the trauma of a major operation, there have been many studies on the transplantation of isolated islets removed from a cadaveric pancreas. There was encouragement from the Edmonton protocol described by Shapiro and colleagues in the New England Journal in 2000. The islets were injected into the portal vein and patients, especially those suffering from dangerous, hypoglycemic unawareness, were treated before they had developed severe complications of diabetes, especially renal complications. While the early results were promising, with some 70% of the patients requiring no insulin injections after two years, at five years, most of these patients had deteriorated and required insulin supplements, despite some having received more than one transplant of islets. In the more recent series of patients, the Edmonton group has reported better long-term results with the use of the monoclonal anti-lymphocyte antibody, Campath 1H given as an induction agent, 45% of patients being insulin-independent at five years, and 75% had detectable C-peptide.

However, cadavaric pancreata and islets compete for the same source and are limited in number, and so, neither treatment could readily be offered to the vast majority of diabetic patients. Some have attempted to use an alternative source, for example, encapsulated islets from neonatal or adult pigs. This is still very experimental and will be a far away alternative with many technical and possibly ethical obstacles to overcome.

More recently, with the successes in the development of pluripotent adult stem cells (from Yamanaka, awarded the 2012 Nobel prize for medicine for developing induced pluripotent stem cells iPSCs), new approaches to seek a methods that may be more accessible and available have been attempted. Much hope was derived initially from embryonic stem cell (ESC) research, since these cells can be persuaded to multiply and develop into any tissue, but the process was expensive, and the problem of teratoma formation from these stem cells proved extremely difficult to overcome. Many of the important factors related to fetal development are not understood and cannot be reproduced. However, some progress has been made, and (occasionally) cells been persuaded to secrete insulin, but so far, there have been very minimal therapeutic application.

Scientists are now aware that to persuade a cell to produce insulin is only one step in what may be a long and difficult journey. Islets cells are highly specialized to have not only a basal release of insulin but also to respond rapidly to changes in blood glucose concentration. With insulin, the process and regulation of switching off secretion is as important as the switching on secretion.

A variety of approaches has been made with different starting points. The stem cell reproduces itself and can then also divide asymmetrically and form another cell type: This is known as differentiation. Although initially they were thought to be available only from embryos, non-embryonic stem cells can now be obtained without too much difficulty from neonatal tissue, umbilical cord, and also from a variety of adult tissues including bone marrow, skin, and fat. These stem cells can be expanded and made to differentiate, but their repertoire is restricted compared with embryonic stem cells: oligo- or pluri- as opposed to toti-potent embryonic stem cells. Even more, recently, there has been much interest in the process of direct cell trans-differentiation, in which a committed and fully differentiated cell, for example a liver cell, is changed directly to another cell type, for example an islet beta-cell, without induction of de-differentiation back to a stem cell stage.

Yamanaka, in 2006, was able to produce pluripotent stem cells from mouse neonatal and adult fibroblast cultures by adding a cocktail of four defined factors.[2] This led to a series of other studies developing the process, which was shown to be repeatable with human tissue as well as laboratory mice. The use of iPS cells avoided the ethical constraints of using human embryos, but there have been other problems and obstacles still. There have been emerging reports of iPS cells becoming antigenic to an autologous or isologous host, and the cells can accumulate DNA abnormalities and even retain epigenetic memory of the cell type of origin and thus have a tendency to revert back. Like embryonic stem cells, iPS cells can form teratoma, especially if differentiation is not complete.

Despite this, there has been very little success in directing differentiation of iPSCs to form islet beta-cells in sufficient quantity that will secrete and stop secretion in response to changes in blood glucose levels.

Another approach that has been tried is to combine gene therapy with stem cells. Some progress has been made in trying to express the desired insulin gene in more primitive undifferentiated cells by coaxing stem cells with differentiation factors in vitro and then by direct gene transfection using plasmids or a viral vector. We, and others, have used a human insulin gene construct and introduced ex vivo or in vivo into cells by direct electroporation (in ex vivo cells obviously) or by viral vectors. The adenovirus, adeno-associated virus, and various retro viruses have been most studied, especially the Lentivirus. However, any type of genetic engineering raises fears not only of infection from the virus but also of the unmasking of onco-genes, leading to malignancy, and there are strict regulations how to proceed to avoid these risks.

We have been interested in umbilical cord stem cells and in mesenchymal stem cells as targets for combined stem cell and gene therapy. These cells can be obtained in a reasonably easy and reproducible manner from otherwise discarded umbilical cord, or readily accessible bone marrow, selecting out the cells using various standard techniques. Fat, amnion, and umbilical cord blood are also sources, from which mesnechymal stem cells can be derived. After a proliferative phase, the cells take up an appearance similar to a carpet of fibroblasts, which can differentiate into bone, cartilage, or fat cells. Although mesenchymal stem cells from the various sources mentioned may look similar, their differentiation potentials are idiosyncratic and differ, which makes it inappropriate and difficult to think of them as a uniform source of target cells. Neonatal amnion cells and umbilical cord cells have low immunogenicity and do not express HLA class II antigens. They also secrete factors that inhibit immune reactions, for example, soluble HLA-G. Although immunogenicity is reduced significantly, they are still not autologous and, therefore, there remains a risk for allograft rejection. They have the advantage that they could be multiplied, frozen, and banked in large numbers and could be used in patients already needing immunosuppressive agents, for examples those having renal transplants.

In Singapore, our studies of umbilical cord-derived amnion cells have shown some success in having expression of insulin and glucagon genes, but little or no secretion of insulin in vitro. Together with insulin gene transfection in vitro, after peritoneal transplantation into sterptozotocin-induced diabetic mice, there was some improvement in glucose levels.[3] Our colleagues in Singapore[4,5] have used another model of autologous hepatocytes from streptozotocin-induced diabetic pigs. These separated hepatocytes were successfully transfected ex-vivo with a human insulin gene construct by electrophoration, and then the cells were injected directly back into the liver parenchyma using multiple separate injections. The pigs were cured of their diabetes for up to nine months - which is a remarkable achievement. As these were autotransplantations, no immunosuppressive drugs were necessary, but the liver cells were obtained from large open surgical biopsies. This necessity of surgical removal of liver tissue would limit its applicability, but nevertheless has been a good proof of concept study. In the context of autoimmune diabetes, the risk of recurrent disease may well persist unless the target of autoimmune attack could be defined and eliminated. In these porcine experiments, the human insulin gene with a glucose sensing promoter EGR-1 was used. There was no virus involved, and the plasmid does not integrate. Division of the transfected cell would dilute gene activity, but large numbers of plasmid can be produced cheaply. The same group of workers successfully transfected bone marrow mesenchymal stem cells with the human insulin gene plasmid using the same EGR-1 promoter and electrophoration. This cured diabetic mice after direct intra-hepatic and intra-peritoneal injection.

Finally, there should be caution in interpreting the results of these and other reports of cell and gene therapy for diabetes. In gene transfection and/or transplantation of insulin-producing cells or clusters in the diabetic rodent, there have been many reports in the literature, but only a few of these claims have been reproduced in independent laboratories. We have suggested the need to satisfy The Seven Pillars of Credibility as essential criteria in the evaluation of claims of success in the use of stem cell and/or gene therapy for diabetes.[1]

Cure of hyperglycemia

Response to glucose tolerance test

Evidence of appropriate C-peptide secretion

Weight gain

Prompt return of diabetes when the transfecting gene and/or insulin producing cells are removed

No islet regeneration of stereptozotocin-treated animals and no re-generation of pancreas in pancreatectomized animals

Presence of insulin storage granules in the treated cells

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Amniotics led consortium selected for EIC-Pathfinder grant of 3.8 million from the European Innovation Council – Marketscreener.com

Amniotics led consortium selected for EIC-Pathfinder grant of 3.8 million from the European Innovation Council  Marketscreener.com

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Amniotics led consortium selected for EIC-Pathfinder grant of 3.8 million from the European Innovation Council - Marketscreener.com

Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics -…

Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics  Marketscreener.com

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Ono Exercises Option to HER2-targeted CAR T-Cell Product Candidate for Solid Tumors Generated from the Collaboration with Fate Therapeutics -...

Cell Rejuvenation and Cell Therapy | Cell Regeneration Perth

There are a lot of theories as to why people change as they get older. Some claim that aging is caused by injuries from ultraviolet light over time, wear and tear on the body, or by-products ofmetabolism. Other theories view aging as a predetermined process controlled by genes.

No single process can explain all the changes of aging. Aging is a complex process that varies as to how it affects different people and even different organs. Most gerontologists (people who study aging) feel that aging is due to the interaction of many lifelong influences. These influences include heredity, environment, culture, diet, exercise and leisure, past illnesses, and many other factors.

Unlike the changes of adolescence, which are predictable to within a few years, each person ages at a unique rate. Some systems begin aging as early as age 30. Other aging processes are not common until much later in life.

Although some changes always occur with aging, they occur at different rates and to different extents. There is no way to predict exactly how you will age.

Some studies have shown that Regeneration treatments have a better effect on people over the age of 35, however this has no clinical evidence to back it up. What we do know is that as we age our bodies do not renew cell turnover at the same rate as it did in our younger years. There appears to be no end age for these treatments to have some effect.

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Cell Rejuvenation and Cell Therapy | Cell Regeneration Perth

cGMP iPSCs & Cell Therapy Manufacturing | CDMO | I Peace, Inc.

For example, pharmaceutical companies and research institutions are conducting research on various diseases, trying to develop new treatments and new drugs. However, progress is limited by the availability of cell samples that can be collected from any one patient. Indeed, a single donors cell sample may not be enough for even one study, in one single institute. Thus, it is often not feasible to expand the scope of a study or allow for others around the world to reproduce or advance results. Without renewable sources of accessible patient cell samples, there is a chronic shortage of research materials, which slows research and development efforts. Many of the inquiries received by I Peace express an eagerness and hope to advance research by providing their iPS-cells to research institutions, but find it difficult as a prospective donor to make such a connection with a research institution. We wish to bridge a prospective donors goodwill and the needs of research institutions by using I Peace platforms.

Since iPS cells can proliferate indefinitely, a patients iPS cells can be grown in large quantities, then differentiated into various cell types. In this case, any cells needed for research could be obtained from a renewable source on demand, such as I Peace, so that research programs are dramatically accelerated.

Similarly, to drive advances in personalized regenerative medicine, I Peace aims to provide donors with accessible and affordable medical-grade personal iPS cells, and with your consent, provide your cells to pharmaceutical companies, research institutions or for joint development programs with I Peace. We believe this partnership, facilitated by I Peace, will accelerate the realization of personalized and autologous transplantation and regenerative medicine for various diseases. We want to build a future that helps patients suffering from these diseases receive new cell-based therapies as soon as possible.

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Stem cell therapy for knees: fact-check, costs, risks

One of the most common questions I get from patients is about stem cell therapy for knees. Can it help knee arthritis and pain? Todays post is a fact-check of where things stand today in 2022 on stem cells for knee issues.

You can watch a video overview of this post on our Stem Cell YouTube Channel below.

Stem cell therapy for knees | Look at the Data |Some biased studies? |Clinical trials: no clear benefit | Cost: $5,000-$10,000 | Risks & Efficacy | 2022 and Looking Ahead | References

Quick Article Summary and Claim Review.Stem cells are a still unproven approach to knee problems like pain and arthritis, but many clinics market this approach, claiming it works and is safe. While risks appear low overall for stem cell knee injections, there have been problems on occasion. The cost of around $5,000-$10,000 at unproven stem cell clinics is not covered by insurance or Medicare. Overall, this experimental therapy may not be worth the cost and risks at this time. More data are needed from ongoing trials. Certain patients are far more likely to benefit from knee replacement instead of stem cells depending on their age and severity of disease, but joint replacement has its own risks. You should consult your doctor.

With all those patients asking about this, perhaps then its not surprising that for-profit clinics have zeroed in. One of the most common claims made by unproven, for-profit stem cell clinics is related to knees.

They sell the idea that their stem cells can help knee arthritis and associated pain, but what is the evidence to back this up? What about other products like platelet rich plasma (PRP) for knees?

There are many problems with the claims of stem cells and other regenerative products.

In many cases what is being sold as stem cells isnt even real stem cells. It often is an amniotic extract.

Such products are probably not made from actual stem cells anyway and are dead.

But what about cases where real, live stem cells are being injected every day for knee arthritis? For other kinds of joint problems? What about PRP?

Mostly the answer seems to be no, with a few maybes.

One of the challenges in this area is that there is so much noise out there. The data are a real jumble.

With just one search on PubMed I found more than 400 articles. Such articles often report conflicting big-picture findings as well.

And there are likely many more articles depending on how one does the literature search.

The first three results popping up with that search are all themselves meta analyses or reviews. I could also easily find many recent clinical trial reports. Many on the surface suggest there might a small benefit to various kinds of stem cell injections, but the studies are often too small or have other issues to be sure. One phrase in this particular study kind of sums up many others: Larger sample size and long-term follow-up are required.

I interpret that to mean that this is not ready for prime time. Its not a convincing replacement for knee joint replacement. While joint replacement has its own issues, the data indicate it gives most patients back the functionality they want.

A Cochrane review of stem cells for knees appears to be ongoing without results so far. It could have a big impact.

Another meta kind of study in the British Journal of Sports Medicine identified potential challenges to many of the regenerative studies on knees. The issue is the risk of bias in many of the stem cell for knees studies. The authors conclude:

Six trials with high risk of bias showed level-3 or level-4 evidence in favour of stem cell injections in KOA. In the absence of high-level evidence, we do not recommend stem cell therapy for KOA.

I know that stem cell clinic doctors can find plenty of studies supposedly supporting what they are offering for knees, but the question is which studies are the strongest? Also, is there some coherent signal of benefit and safety rising above the noise overall? I didnt see it.

Many universities and medical centers including the Mayo Clinic are studying stem cells for various orthopedic injuries including knee problems. These clinical trials so far have not produced clear data supporting regenerative approaches as a new standard of care.

Some reasons include that some trials to date havent been designed or powered to measure efficacy, other trials produced inconclusive results, and many trials are still ongoing. As to the first reason, an example is The completed Phase 1 Mayo Clinic trial.This study of bone marrow stem cells for knees was very preliminary.

The published Mayo study itself was direct about the inconclusive results:

Study patients experienced a similar relief of pain in both BMAC- and saline-treated arthritic knees.

In other words, the stem cells did nothing more than just an injection of salt water.

A search I did on Clinicaltrials.gov found more than 100 listings of studies of stem cells for knees. I did the search on March 29, 2021.

Other trials are examining PRP for knee issues. PRP could actually be more promising here than MSC-type cells as they are currently being used.

The CIRM Blogrecently covered the issue of stem cells for knee arthritis at clinics. In large part the post seemed inspired by a new at that time comprehensive study that sheds major doubt on this approach.

Some of the main take-homes from the study on clinics were nicely summarized by Kevin McCormack of CIRM, including on cost:

In a study presented at the Annual Meeting of the American Academy of Orthopaedic Surgeons, researchers contacted 317 clinics in the US that directly market stem cell therapies to consumers. They asked the clinics for information on the cost of the procedure and their success rate.

Only 36 clinics responded with information about success rates.

None offered any evidence based on a clinical trial that supported those claims, and there was no connection between how much they charged and how successful they claimed to be.

Patients are paying around $5K-$10K for a kind of stem cell treatment where clinics are largely claiming 70-100% success yet have little or no strong clinical trial evidence to back it up. The average cost data here fit wellwith the numbers in a poll I did on The Niche of what patients say they paid for stem cell therapies more generally. Note that this approach is not covered by insurance or Medicare.

McCormack has quotes both from the lead authors,Nicolas Piuzzi andGeorge Muschler, of the study entitled, The Stem-Cell Market for Treatment of Knee Osteoarthritis: A Patient Perspective, which is published in Journal of Knee Surgery with some big picture perspectives and thoughts on the meaning of their work. Check it out.

Basically, theres a disconnect between the state of the clinical science in this area and what is being widely marketed for profit. Im not aware of massive patient side effects in this area so safety, while not assured by any means, is perhaps not the biggest issue.

Risks. A possible risk comes from poor injection methods. I have had patients report that injections to the knee went badly after the needle ended up outside the knee joint. Some clinics using imaging to guide the process so thats a plus. Many are not. Probably the other main risk is infection. It is unclear if the stem cell materials themselves pose specific risks like incorrect tissue growth.

Efficacy. Overall, there is minimal evidence of efficacy from properly controlled studies. For instance, the authors ofthis stem cells for knees studysuggest potential benefit of bone marrow stem cells for knee arthritis, but although it did have a control group, it wasnt blinded and was underpowered.Heres a more recent, blinded studyarguing for some moderate benefit, but it was underpowered as well and no benefit was seen after 12 months. Clinics will point to yet other studies that purportedly report benefits, but the big picture is just not very clear.

I hope in the future we get that data as a field so we can have better clarity here. You can see some past posts including on knee arthritis. Its apparent that for up to 8 years or more this issue has been percolating.

Other alternatives including knee replacements, especially for older patients, can offer great outcomes. The Mayo Clinic and others are using approaches beyond stem cells. They are also testing approaches using cartilage cells called chondrocytes instead of stem cells, which also show promise.

My viewis that stem cell injections for knee arthritis from clinics directly marketing to consumers is most often going to be a big waste of money for patients and again there are risks. This is not to say that theres no hope of stem cells for arthritis or specifically for knee arthritis, but caution is in order right now on this front.

Im optimistic about the future of this area, but most of whats going on now commercially is not ready for prime time.

Disclaimer: this post is not medical advice. Consult with your doctor before making medical decisions.

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Stem cell therapy for knees: fact-check, costs, risks

Global Cell Banking Outsourcing Market to Grow at a CAGR of ~18% during 2022-2031; Market to Expand Owing to the Development of Advanced Cell…

New York, Aug. 23, 2022 (GLOBE NEWSWIRE) -- Kenneth Research has published a detailed market report on Global Cell Banking Outsourcing Market for the forecast period, i.e., 2022 2031, which includes the following factors:

Global Cell Banking Outsourcing Market Size:

The global cell banking outsourcing market generated the revenue of approximately USD 7200.1 million in the year 2021 and is expected to garner a significant revenue by the end of 2031, growing at a CAGR of ~18% over the forecast period, i.e., 2022 2031. The growth of the market can primarily be attributed to the development of advanced preservation techniques for cells, and increasing adoption of regenerative cell therapies for the treatment of chronic diseases such as cancer. Additionally, factors such as growing demand for gene therapy, and increasing worldwide prevalence of cancer are expected to drive the market growth. According to the World Health Organization, nearly 10 million people died of cancer across the globe in 2020. The most recurrent cases of deaths because of cancer were lung cancer which caused 1.80 million deaths, colon, and rectum cancer which caused 916 000 deaths, liver cancer which caused 830 000 deaths, stomach cancer which caused 769 000 deaths, and breast cancer which caused 685 000 deaths. Furthermore, it was noticed that about 30% of cancer cases in low and lower-middle income nations are caused by cancer-causing diseases such the human papillomavirus (HPV) and hepatitis.

Get a Sample PDF of This Report @ https://www.kennethresearch.com/sample-request-10070777

Global Cell Banking Outsourcing Market: Key Takeaways

Increasing Geriatric Population across the Globe to Boost Market Growth

Increasing demand for stem cell therapy, and increasing biopharmaceutical production are estimated to fuel the growth of the global cell banking outsourcing market. Among the geriatric population around the world, the demand of stem cell therapy is at quite a high rate. Hence, growing geriatric population across the globe is also expected be an important factor to influence the market growth. According to the data by World Health Organisation (WHO), the number and proportion of geriatric population, meaning the people aged 60 years and older in the population is rising. The number of people aged 60 years and older was 1 billion in 2019. This number is estimated to increase to 1.4 billion by 2030 and 2.1 billion by 2050.

In addition to this, increasing prevalence of chronic diseases, supportive initiatives by governments around the world, and growing awareness about stem cell banking are predicted to be major factors to propel the growth of the market. The growth of the global cell banking outsourcing market, over the forecast period, can be further ascribed to the rising investments in the R&D activities to continuously bring up more feasible solutions for medical procedures. According to research reports, since 2000, global research and development expenditure has more than tripled in real terms, rising from approximately USD 680 billion to over USD 2.5 trillion in 2019.

Browse to access In-depth research report on Global Cell Banking Outsourcing Market with detailed charts and figures: https://www.kennethresearch.com/report-details/cell-banking-outsourcing-market/10070777

Global Cell Banking Outsourcing Market: Regional Overview

The global cell banking outsourcing market is segmented into five major regions including North America, Europe, Asia Pacific, Latin America, and the Middle East and Africa region.

Advanced Healthcare Facilities Drove Market in the North America Region

The market in the North America region held the largest market share in terms of revenue in the year 2021. The growth of the market in this region is majorly associated with the increasing number of pharmaceutical companies & manufacturers in the region, and increasing awareness for the use of stem cells as therapeutics. Increasing number of bone marrow and cord blood transplants throughout the region is also estimated to positively influence the market growth. It was noted that, 4,864 unrelated and 4,160 related bone marrow and cord blood transplants were performed in the United States in 2020.

Increasing Prevalence of Chronic Diseases to Influence Market Growth in the Asia Pacific Region

On the other hand, market in the Asia Pacific region is estimated to grow with the highest CAGR during the forecast period. The market in this region is driven by the increasing investment in biotechnology sector by government and private companies specifically in countries such as China, India, and Japan. Moreover, the increasing pool of patient with chronic diseases, such as cancer, and the ongoing research & development activities for cancer treatment is expected to propel the growth of the market. Further, increasing percentage of regional health expenditure contributing to the GDP is also estimated to be a significant factor to influence the growth of the cell banking outsourcing market in the Asia Pacific region. As per The World Bank, in the year 2019, share of global health expenditure in East Asia & Pacific region accounted to 6.67% of GDP.

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The study further incorporates Y-O-Y growth, demand & supply and forecast future opportunity in:

Middle East and Africa (Israel, GCC [Saudi Arabia, UAE, Bahrain, Kuwait, Qatar, Oman], North Africa, South Africa, Rest of Middle East and Africa).

Global Cell Banking Outsourcing Market, Segmentation by Bank Phase

The bank storage segment held the largest market share in the year 2021 and is expected to maintain its share by growing with a notable CAGR during the forecast period. The market growth is anticipated to be driven by the development of effective preservation technologies such as cryopreservation technique. Cryopreservation is a technique in which low temperature is used to preserve the living cells and tissue for a longer time. With the growing healthcare expenditure per capita across the world, demand for bank storage increasing notably. As sourced from The World Bank, in 2019, worldwide health expenditure per capita was USD 1121.97.

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Global Cell Banking Outsourcing Market, Segmentation by Product

The adult cell banking segment is estimated to hold a substantial market share in the global cell banking outsourcing market during the forecast period. The growth of this segment can be attributed to the significant prevalence of chronic diseases among the adults around the globe. For instance, according to the National Library of Medicine 71.8% of adult population suffered from cardiovascular diseases, 56% had diabetes, and 14.7% adults had arthritis as of 2020.

Global Cell Banking Outsourcing Market, Segmentation by Cell Type

Global Cell Banking Outsourcing Market, Segmentation by Bank Type

Few of the well-known market leaders in the global cell banking outsourcing market that are profiled by Kenneth Research are SGS SA, WuXi AppTec, LifeCell International Pvt. Ltd., BSL Bioservice, LUMITOS AG, Cryo-Cell International, Inc., REPROCELL Inc, CORDLIFE GROUP LIMITED, Reliance Life Sciences, and Clean Biologics and others.Enquiry before Buying This Report @ https://www.kennethresearch.com/sample-request-10070777

Recent Developments in the Global Cell Banking Outsourcing Market

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Global Cell Banking Outsourcing Market to Grow at a CAGR of ~18% during 2022-2031; Market to Expand Owing to the Development of Advanced Cell...

Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? – Forbes

Nearly twenty-five years ago, the scientific breakthrough of mammalian cloning marked a monumental moment in medicine and science. Anticipating the collision it would have with ethical decision making in medicine, I, the only physician-scientist in the U.S. Senate at the time, journeyed to the University of Edinburgh in Scotland to personally visit Sir Ian Wilmut at his research lab at the Roslin Institute.

My house call to Dolly in 1997: I stand with Dolly, the first ever mammal to be cloned from an adult ... [+] somatic cell, during my journey to visit her creator and caretaker, Sir Ian Wilmut.

Professor Wilmut just months before in 1996 had cloned a sheep from an adult somatic cell, shocking the world. This was the first successful attempt of its kind. All over the world people were wondering: would we be cloning a human being next? We talked science, we talked ethics, and we talked about his creations potential impact on altering the course of human history. I also met and examined the cloned sheep, Dolly, in her stall.

Dolly, named after Tennessees own Dolly Parton, was a Finnish Dorset sheep cloned from a single, adult mammary gland cell. Her creation, birth, and short life were scientific feats that immediately sparked global concern and discourse on the increasingly complex moral and ethical dilemmas posed by a sudden discovery of life-manipulating science.

Wilmut and colleagues published their achievement in February 1997, having kept Dolly secret for seven months. We, as a society, were quickly forced to answer difficult, probing questions. A few months later on the Senate floor, I borrowed a question that the Washington Post editorial board had posed a few years before: Is there a line that should not be crossed even for scientific or other gain, and if so where is it?

Here are my remarks in the Senate chamber in 1998:

So it is vital that our public debate and reflection on scientific developments keep pace, and even anticipate and prepare for new scientific knowledge. The moral and ethical dilemmas inherent in the cloning of human beings may well be our greatest test to date. We do not simply seek knowledge, but the wisdom to apply that knowledge. As with each of the mind-boggling scientific advances of the last century, we know that there is the potential for both good and evil in this technology. Congressional Record February 2, 1998

Years removed, I now reflect back on the confusion, questions, and status quo that Dolly challenged.

Dolly was the first mammal to be successfully cloned from an adult somatic cell, which is any type of bodily cell that is not a reproductive germ cell. The process Wilmut developed is technically called somatic cell nuclear transfer, colloquially known as cloning. It is the process of transferring the nuclear DNA of a donor somatic cell into an enucleated oocyte, followed by embryo development and then transfer to a surrogate recipient, followed by live birth.

Dollys creation in a test tube and eventual birth marked a major milestone in scientific research, suggesting that an animal could be cloned to create an exact replica using genetic material derived from theoretically any type of body cell. It opened the world to staggering new possibilities in reproductive cloning and therapeutic cloning.

Soon after Dollys birth, another parallel and similarly monumental finding was made: in 1998 embryonic stem cells were discovered. These cells are a highly unique type of unprogrammed somatic cell with the exceptional ability to both reproduce unlimited exact copies of themselves and develop into more specialized cell types, such as heart, lung, kidney or skin cells. And though seemingly miraculous in potential, these cells could not be created or programmed from any other type of cell and could only be collected from embryos an ethical dilemma because collection for research required destruction of the embryo itself.

Dolly changed this. Her successful creation paved the way for future scientists to develop a technique to independently produce equally powerful pluripotent stem cells by reprogramming other adult somatic cells, revolutionizing genetic therapy, and completely nullifying the ethical dilemma of collecting embryonic stem cells from embryos. Similarly, Dolly also highlighted the potential for scientists to create new tissues and organs for diseased patients, and to preserve the genetic material of endangered species.

But, along with these positive contributions came widespread concern about the ethics of cloning, especially around potential attempts to clone another human being. Many, including myself, feared this type of technology, if left unregulated, would be misused and abused. Indeed, cloning evoked great scientific power that demanded even greater ethical responsibility, and there were no established ethical guardrails at the time to monitor this duty.

In retrospect, these fears have diminished in part due to proactive measures and to the inherent complexities of the human genome (cloning an entire human being is, after all, a large jump from cloning a sheep). Importantly, legislative and scientific communities have been resolute and unified in their opposition to cloning human beings.

Though a human embryo was indeed successfully cloned in 2013, no known progress has been made when it comes to attempts to clone a human being. Yet the technique to create Dolly has been repurposed widely and has led to numerous scientific innovations.

In 2003, six years after her birth, Dolly became sick and was euthanized. Her decline in health was due to the development of tumors in her chest; some examinations of her cells suggested that she was also aging prematurely.

Despite her relatively short life (the average sheep lifespan is ~10-12 years), Dollys influence on the scientific community has been profound. Not only did she force scientists and researchers to redefine the ethics of their field, but she also laid the foundation for other significant scientific advancements in the fast-evolving new field we know today as regenerative medicine.

One powerful example is gene therapy and editing, where specific genes are targeted, edited, and repaired to protect against disease, cancer, autoimmune disorders, and even rewiring immune system cells for treatment-resistant cancer patients. This revolutionary innovation is made possible by CRISPR technology (the same technology that enabled rapid vaccine development for COVID-19), which is currently celebrating its 10-year anniversary.

Genetic cloning was also made possible thanks to Dolly. This is a type of cloning where scientists create copies of genes within DNA segments to combine with plasmid DNA, or self-replicating genetic material, and then place this new plasmid into a host organism, such as a bacterium, yeast, or mammal cell. This process is used to develop vaccines and antigen tests and is also used to identify useful genetic traits in plants, which can be replicated on a larger scale through the genetic modification of seeds.

Further, cloning techniques have also helped to advance agricultural practices. Farmers can use cloning technology to quickly introduce favored characteristics of prize livestock (such as the ability to produce large amounts of high-quality milk) into a herd by cloning and breeding. These livestock will then further reproduce using traditional breeding or assisted reproductive technology.

Despite advances in genetic cloning and agricultural practices, cloning especially the additional attempts at cloning whole organisms remains variable and highly inefficient.

Successful attempts have been made by companies like Sooam Biotech Research and ViaGen Pets to clone dogs and kittens for wealthy pet owners. But, even today, the success rate of animal cloning is estimated to be less than 30%. In fact, many animal rights activists oppose the practice citing animal welfare. In 2015, the European Union banned the practice of livestock cloning.

Overall interest in cloning slowed as advances in adult stem cell research gained traction in the 2000s. This resulted primarily from scientists newfound ability to take adult human cells, for example skin cells, and reprogram them back into an earlier, more primitive but more powerful embryonic-like, pluripotent cells.

This technique was pioneered by Japanese scientist Shinya Yamanaka in 2006, for which he was awarded the 2012 Nobel Prize in Physiology or Medicine. Yamanakas discovery of reprogramming already specialized adult cells to create induced pluripotent stem cells (IPS) took the ethical issue of destroying embryos for research off the table. Some scientists continue to look to cloning as a way to develop genetically unique stem cells that can be used to reduce the risk of triggering an immune response.

Notes taken shortly after my visit with Dolly.

We have come a long way since my exploratory journey from the Senate floor in Washington, DC, to the stall and research laboratory that housed Dolly in Edinburgh in 1997.

For all the controversy that Dolly sparked during her short life, her contributions to society have been nothing short of remarkable. She forced thought leaders, researchers, and policymakers around the world to confront the ethics of cloning. And, she encouraged us, as a society, to weigh in and engage on the ethical considerations of increasingly frequent scientific discoveries.

On all of these fronts, we worked tirelessly to instill and adhere to a strong scientific code, focusing on the bettering of science, innovation, and technology for societal good. Cloning gave us that first glimpse into the future.

As I said on the floor of the Senate on February 3, 1998:

This cloning debate, I think, maybe for the first time in the history of this body [the US Senate], forces us to address what is inevitable as we look to the future, and that is a rapid-fire, one-after-another onslaught of new scientific technological innovation that has to be assimilated into our ethical-social fabric. Congressional Record February 3, 1998

What I said then still holds true today, Science and ethics must march hand in hand. Congressional Record February 11, 1998

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Twenty-Five Years After My House Call To Dolly: What Have We Learned About Cloning And How Did We Learn It? - Forbes

Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes | Scientific Reports -…

The landscape of genetic variation of DENRGs in GC

A total of 48 DENRGs were identified using limma package for further analysis (p<0.05, Fig.1A). Out of 433 GC samples, 147 (33.95%) were showed regulatory mutations associated with necroptosis (Fig.1B) and ATRX (5%) was the highest frequency mutated gene. As loss or gain of function is commonly achieved through DNA mutation or amplification/deletion, we considered both somatic mutation and somatic copy number changes in our analysis. We first summarized the incidence of copy number variations and somatic mutations of 48 DENRGs in GC. The frequency of CNV alterations and found that all 48 DENRGs showed prevalent CNV alterations (Fig.1C). The rates of amplification or deletion for most of DENRGs were relatively low. The altered position of CNVs of DENRGs on chromosome were also scanned and illustrated with visual figure (Fig.1D). In addition, most of the DENRGs were significant increase in tumor tissues (Fig.1E).

The landscape of genetic alterations of DENRGs in GC. (A) Heatmap of DENRGs expression between the normal and tumor samples. Blue represents normal gastric tissue, pink represents tumor tissue; upregulated genes were defined as red, and downregulated genes as blue. (B) Mutation characteristics of DENRGs in the TCGA-GC cohort. The TMB is presented in the barplot at the top of the image; the mutation frequency of each DENRGs is indicated on the barplot right. The barplot on the right represents different mutation types proportions. (C) CNV variants frequency of the DENRGs in the TCGA-GC cohort. Red: amplification frequency. Green: loss frequency. The column represented the alteration frequency. (D) The locations of CNV alteration of DENRGs on 23 chromosomes. (E) Expression of DENRGs between normal gastric tissue and tumor tissue. Blue: normal gastric tissue. Red: tumor tissue. DENRGs, differentially expressed necroptosis-related genes. (*p<0.05; **p<0.01; ***p<0.001).

To further explore the interactions of these DENRGs, we conducted a PPI analysis, and the PPI network was shown in Fig. S1A. In addition, the correlation network containing all DENRGs was presented in Fig. S1B. The network above indicated that there was a very strong correlation among DENRGs. GO-term analysis showed that DENRGs were associated with necrotic cell death, programmed necrotic cell death, necroptotic process and apoptotic signaling pathway (Fig. S2A). KEGG pathway analysis displayed that these DENRGs were involved in multiple tumor-related signaling pathway including necroptosis, apoptosis, TNF signaling pathway, IL-17 signaling pathway, and Toll-like receptor signaling pathway (Fig. S2B).

According to Consensus clustering analysis, when the clustering variable was set to the optimal value (K=2), the intragroup correlations were the highest, and the intergroup correlations were the lowest, indicating that all GC patients could be classified into two molecular subtypes (Figs.2A, S3A and S3B), which were termed as C1 (n=208) and C2 (n=163). The heatmap demonstrated a significant difference between cluster C1 and C2 in clinical factors including tumor grade and T stage (Fig.2B). Result of KaplanMeier curve analysis revealed that the patients in C2 cluster had a poorer prognosis (Fig.2C). The results above indicated that the necroptosis subtypes classified by consensus clustering analysis do well in distinguishing prognosis of those GC patients.

Tumor molecular subtypes related by differentially expressed necroptosis-related genes. (A) Consensus clustering of GC patients for k=2 in the meta-cohort (TCGA-GC and GSE84437). (B) Unsupervised clustering heatmap of top 100 DEGs in GC. Clusters, age, gender, grade and stage were used as patient annotations. Red represents high DEGs expression and blue low DEGs expression. *p<0.05; **p<0.01; ***p<0.001. (C) KaplanMeier curves (Log-rank test, P=0.004) for OS of two necroptosis-related molecular subtypes. Blue line represents cluster C1 (n=208), yellow line represents cluster C2 (n=163). DEGs, differentially expressed genes between various molecular subtypes; OS, overall survival.

Given the clear importance of the TME in tumorigenesis, we further investigated whether the two subtypes showed differential characteristics of immune microenvironment and the main results presented in Fig.3AH. The abundance of immune infiltrating cells, including resting Dendritic cells, resting Mast cells, T cells regulatory (Tregs), Monocytes and M2 macrophages, were found significantly higher in the C2 subtype. And M1 macrophages, T cells follicular helper and activated T cells CD4 memory in C1 subtypes showed greater infiltration. These results suggested that the two molecular subtypes associated with necroptosis had distinct TME infiltration characteristics and prognoses.

TME immune cell infiltration levels between two molecular subtypes. The abundance of Monocytes (A), resting Mast cells (B), M2 macrophages (C), M1 macrophages (D), resting Dendritic cells (E), T cells regulatory (Tregs) (F), T cells follicular helper (G) and activated T cells CD4 memory (H) between the two subtypes (all p<0.05). Blue represents cluster C1, red represents cluster C2. The median value is represented as the thick line, and the interquartile range is represented as the box bottom and top. Scattered dots represent outliers.

To better understand the mechanisms responsible for the prognosis differences in the two above molecular subtypes, we further investigate the functional and pathway and 1101 DEGs associated with necroptosis phenotypes were identified by the limma package. GO analysis showed an enrichment of GO terms for these DEGs, including extracellular matrix organization, collagen containing and extracellular matrix binding (Fig.4A). KEGG pathway analysis for the DEGs showed that genes involved in immune-related pathways were enriched, including ECM-receptor interaction, Focal adhesion, and TGF-beta signaling pathway (Fig.4B). These results reconfirmed a pivotal role of necroptosis in regulating the immune microenvironment.

Functional enrichment analysis of the DEGs. (A) Top 10 enriched GO terms of the DEGs (B) Top 10 enriched KEGG pathways of the DEGs. The box color represents the number of enriched genes. Red represents a large number of genes enriched; blue is the opposite. DEGs differentially expressed genes, BP biological process, CC cellular component, MF molecular function. (all adjusted p<0.05).

Although our results identify a role of necroptosis molecular subtypes in prognosis and regulation of immune infiltration, these analyses are based only on patient groups and cannot be used to predict the necroptosis characteristics in individual GC patients. For this, we next constructed an multigenic prognostic signature associated with prognosis and response to treatment in each GC patient based on differential genes of molecular subtypes. We performed univariate Cox regression analysis on all DEGs and resulted in 84 genes as candidate genes (all P<0.005; Fig.5A). Most of the candidate genes were risk factors for the prognosis of GC except for MYB and RNF43. We then subjected the candidate genes to LASSO Cox regression analysis by narrowing the number of genes for the establishment of the NRGsig (Fig.5B and C). In total, 11 optimal genes (CYTL1, PLCL1, CGB5, ADRA1B, APOD, RGS2, CST6, MATN3, RNF43, SLC7A2 and SERPINE1) were screened (Table 2) and most of the optimal genes were significant differentialexpression between the normal tissue and tumor tissue (Fig. S4). The formula of the risk score was calculated as follow:

$$begin{gathered} Risk; score = CYTL1 {text{exp}}.; times ;0.05351 ; + ; PLCL1 {text{exp}}.; times ;0.06101 ; + ; CGB5 {text{exp}}.; times ;0.1605 hfill \ quad quad quad quad , + ; ADRA1B {text{exp}}.; times ;0.07886; + ;APOD {text{exp}}.; times ;0.03166; + ;RGS2 {text{exp}}.; times ,0.04199, + ;CST6 {text{exp}}. hfill \ quad quad quad quad , times ;0.00119 ; + ;MATN3 {text{exp}}.; times ;0.13379 ; + ;RNF43 {text{exp}}.; times ; - 0.09577; + , SLC7A2 {text{exp}}. times ;0.07123. hfill \ quad quad quad quad , + ;SERPINE1 {text{exp}}.; times ;0.12925 hfill \ end{gathered}$$

The development of NRGsig in the TCGA-GC cohort. (A) The prognostic-related genes determined by univariate Cox-regression analysis. Red represents risk genes; green represents protective genes. (B) LASSO regression of prognostic-related genes. (C) Crossvalidation for tuning the parameter selection.

All GC patients were divided into high- and low-risk score group according to the median risk score value. Next, we investigated whether the prognostic signature could distinguish different risk groups of patients clearly. A clearly discernable dimensions between the two risk groups of patients was observed according to the results of PCA and t-SNE analysis (Fig.6A and B). KaplanMeier curves analysis revealed high-risk group patients had a worse prognosis. (Fig.6C). The time-dependent ROC curves were performed to evaluate the prediction performance of the NRGsig and the areas under the curve for 5-year was 0.743 in the TCGA-GC cohort (Fig.6D). Results above demonstrated NRGsigs advantage as robust tool for prognosis.

Prognosis value of necroptosis-related prognostic signature in the TCGA-GC cohort. (A) Principal component analysis plot. (B) T-distributed neighbor embedding plot. (C) KaplanMeier curves (Log-rank test, P<0.001) for OS of high- and low-risk groups. (D) The AUC of the prediction of 1, 3, 5year survival rate of GC. OS, overall survival.

We externally validated the NRGsig using the GSE84437 dataset, an independent validation dataset, and found a similar prediction performance. Patients were then classified as being high or low risk according to the calculated NRGsig risk score. A clearly two directions between the two risk groups of patients was also observed according to the results of PCA and t-SNE analysis (Fig.7A and B). KaplanMeier curves analysis indicated high-risk group patients had a worse outcome (Fig.7C). This independent validation dataset yielded a prediction performance AUC of 0.623 at 5-year (Fig.7D). As a whole, these results showed a satisfactory prediction performance of the NRGsig in external data.

Validation of the necroptosis-related prognostic signature in the GSE84437 cohort. (A) Principal component analysis plot. (B) T-distributed neighbor embedding plot. (C) KaplanMeier curves (Log-rank test, P=0.005) for OS of high- and low-risk groups. (D) The AUC of the prediction of 1, 3, 5year survival rate of GC. OS, overall survival.

The independence of NRGsig were evaluated by univariate and multivariate Cox regression analysis and the result revealed the NRGsig was an independent prognostic factor of GC (Fig.8A and B). Above analysis were repeated in the GSE84437 cohort and similar results were observed (Fig.8C and D). Furthermore, the clinical features in the different risk groups for TCGA-GC cohort we depicted as a heatmap (Fig.8E). To verify the clinical implications of our NRGsig risk score, we examined the correlation of the risk score with the available clinical features in TCGA-GC cohort. The KaplanMeier curves indicated that risk score remained its independent predictive performance regardless of other clinical features, including age (60 or>60years), sex (female or male), grade (G1-2 and G3), T-stage (T3-4), N-stage (N0 and N1-3), and M-stage (M0) (Fig. S5AL). Survival analysis demonstrated that these 11 optimal genes were all correlation with the OS of GC patients (Fig. S6AK). All the results above illustrated that NRGsig was a satisfactory and reliable prognostic tool and could be as an independent risk factor for GC.

Independent prognosis analysis. (A, B) Univariate Cox regression analysis in the TCGA-GC cohort. (C, D) Multivariate Cox regression analysis in the GSE84437 cohort. (E) Heatmap depicting the clinicopathological characteristics and optimal genes expression between the high- and low-risk groups. Risk, age, gender, grade and stage were used as patient annotations. Red represents high expression and blue low expression. *p<0.05; **p<0.01; ***p<0.001.

After categorizing cases of TCGA-GC cohort into two risk score groups by the median risk score value, we further performed GSEA analysis towards them. The results of GSEA suggested that the KEGG_COMPLEMENT_AND_COAGULATION_CASCADES, KEGG_ECM_RECEPTOR_INTERACTION, KEGG_FOCAL_ADHESION, KEGG_HYPERTROPHIC_CARDIOMYOPATHY_HCM, and KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION were the top five most enriched pathways in the high-risk group, while the KEGG_CELL_CYCLE, KEGG_DNA_REPLICATION, KEGG_BASE_ EXCISION_REPAIR, KEGG_RIBOSOME, and KEGG_SPLICEOSOME pathways were most enriched in the low-risk group (Figs. S7A and B).

To make the prognosis tool more convenient and quantitative, we integrated risk score with other clinical features including Age and TNM stage to establish a nomogram followed by a series of performance testing (Fig.9A). The net benefit of nomogram was better than other clinical factors, a clinical value was observed as our expectations (Fig.9B). The ROC curve analysis revealed that nomogram had an advantage over other single predictors. In addition, an excellent consistency with ideal model could be observed in the subsequent calibration plot of nomogram for OS predicting (Fig.9C and D). Furthermore, to evaluate the prediction performance of the NRGsig for clinical applications in the TCGA-GC cohort, we compared our prognostic signature with other GC signatures reported in 2020 (Dai signature, Guan signature, Liu signature and Shao signature, respectively). We adopted similar risk score-estimated method described above towards these four signatures to generate risk score for samples from TCGA-GC cohort. The time-independent ROC curves illustrated that Liu signature, Shao signature and Guan signature exhibited lower AUC values for 1-, 3- and 5-year survival rates than NRGsig. The Dai signature presented similar AUC values with our signature (Fig. S8AE). Similar to our signature, these four signatures could also predict the OS of GC patients except for Liu signature and shao signature (Fig. S8GJ). Moreover, the C-index of the NRGsig was the higher than other four signatures (Fig. S8K). NRGsig evidenced its advantage in long-term survival predicting and risk stratification compared with other four prognostic signatures.

The construction and assessment of nomogram. (A) Nomogram integrating clinical factors and risk score for predicting 1-, 3-, and 5-year OS in TCGA-GC cohort (B) Decision curves of risk score, nomogram, and single clinical factors including T stage, N stage and age. (C) The time-dependent ROC curves of risk score, nomogram and single clinical factors including T stage, N stage and age. (D) The calibration curves for 1-, 3-, and 5-year OS. OS, overall survival.

In line with our aim to increase the response to immunotherapy, we investigated the potential correlates between immune infiltration of tumors and NRGsig risk score. After calculating the infiltrating score of 16 immune cells and 13 immune-related pathways by using ssGSEA, we observed significantly increased antigen presenting function including aDCs, DCs and APC co-stimulation score in the high-risk group, while the activity of APC co-inhibition and MHC class I showed the opposite variation (all adjusted P<0.05). Besides, contents of Treg cells, TIL cells and T helper cells were relatively higher in high-risk group, while the activity of Th2 cells had exactly the reverse results. Those results suggested significant difference in T cell regulation between the two subgroups. Moreover, CCR, mast cells, B cells, macrophages, neutrophils, parainflammation, type I IFN response and type II IFN response were observed to have increasing activities in samples from high-risk group (Fig.10A and B). Similar observational results existed for in the GSE84437 cohort (Fig.10C and D). Taken together, the findings of this study demonstrated that different risk groups have different immune landscape, which affected the prognosis of GC patients.

ssGSEA scores in the high- and low-risk group in the TCGA-GC and GSE84437 cohort. (A, B) TCGA cohort, (C, D) GSE84437 cohort. The scores of 16 immune cells (A, C) and 13 immune-related functions (B, D) are displayed in boxplots.

We next explored potential expression changes of immune checkpoints between high- and low-risk groups. Results showed clear differences between the two patient groups, such as BTLA, CD86, CD200, CD27, and other immune checkpoints (Fig. S9). These results highlighted NRGsig as a therapeutic potential for combination strategies with immune checkpoint blockade (ICB) therapy in GC patients. Beyond ICB therapy, we also investigated sensitivity of chemotherapeutic and targeted therapeutics agents between high- and low-risk score groups in TCGA-GC cohort. Results indicated that IC50 toward eleven chemotherapeutics including A.770041, AS601245, AZ628, Axitinib, Luminespib, Navitoclax, Motesanib, Ponatinib, Rucaparib and Saracatinib, of samples in low-risk group were higher than those of high-risk group except for Veliparib (P<0.05), suggesting that samples in low-risk group were more responsive to those medicine (Fig.11AK). As mentioned already, GSEA analysis revealed that a drug-resistant pathway like KEGG_BASE_EXCISION REPAIR was highly enriched in the low-risk score group, which could partially explain the above results. Drugs sensitivity analysis suggested that high-risk score patients might be more suitable for chemotherapy better response to chemotherapy.

Drugs sensitivity analysis in patients from different risk score groups. The sensitivity to chemotherapeutic drugs was represented by the half-maximal inhibitory concentration (IC50) of chemotherapeutic drugs. (AK) Comparisons of IC50 for chemotherapeutics drugs between two subgroups revealed that the high-risk group was more likely to benefit from the treatments (KruskalWallis test, all p<0.01).

Evidence is growing that high TMB is a feature associated with response to immunotherapy in a variety of tumors, and high TMB levels lead to an increase in tumor neoantigens, which may trigger the immune system to attack the tumor40,41. Thus, we assessed the correlation of risk score with TMB in the TCGA-GC cohort. A negative relationship was observed between them, and the TMB score of the two risk groups were evaluated and significant disparity could be observed. The results illustrated that low-risk group patients had a significantly higher TMB than high-risk group (Fig.12A). The combination of high TMB and low-risk score had the best OS in GC by KaplanMeier curves (Fig.12B).

Correlation of risk score with TMB and predictive value of risk score for immunotherapy response. (A) TMB differences between the high- and low-risk score groups and the scatter plot depicted a positive correlation between risk score and TMB. (B) KaplanMeier curves for patients stratified by risk score and TMB in the TCGA-GC cohort. (CE) Immunophenscore (IPS) between high- and low-risk score groups. Blue represents the low-score group and red the high-score group. The thick line within the violin plot represents the median value. The inner box between the top and bottom represents the interquartile range. (C) IPS score when PD-1 positive; (D) IPS score when CTLA4 positive; (E) IPS score when both PD-1 and CTLA4 positives. TMB, tumor mutation burden; IPS, Immunophenscore. (F) TIDE score differences between the high- and low-risk score groups and the scatter plot depicted a positive correlation between risk score and TIDE and lower risk score may be more likely to benefit from the immunotherapy (Spearman text, p<0.001).

Furthermore, we explored the potential of risk score as predictor for immunotherapy response. We applied two mature algorithms, including IPS and TIDE, to predict the response of GC samples with different risk score to immunotherapy. The result evidenced that the IPS value for CTLA4 or PD1 therapy response was more sensitive in the low-risk group and suggested that the NRGsig has high potentiality for predicting CTLA4 and PD1 blockade therapy (Fig.12CE). On the other hand, the TIDE score was higher in the low-risk group and was also positively correlated with risk score, which indicated the lower risk score might benefit more from immunotherapy (Fig.12F and G). Two distinct algorithms drew consistent results. The results above implied that NRGsig may effectively help predict the response to immunotherapy.

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Construction of a novel signature and prediction of the immune landscape in gastric cancer based on necroptosis-related genes | Scientific Reports -...

Gene & Cell Therapy FAQs | ASGCT – American Society of Gene & Cell …

For more in-depth learning, we recommend Different Approaches in our Patient Education program.

The challenges of gene and cell therapists can be divided into three broad categories based on disease, development of therapy, and funding.

Challenges based on the disease characteristics: Disease symptoms of most genetic diseases, such as Fabrys, hemophilia, cystic fibrosis, muscular dystrophy, Huntingtons, and lysosomal storage diseases are caused by distinct mutations in single genes. Other diseases with a hereditary predisposition, such as Parkinsons disease, Alzheimers disease, cancer, and dystonia may be caused by variations/mutations in several different genes combined with environmental causes. Note that there are many susceptible genes and additional mutations yet to be discovered. Gene replacement therapy for single gene defects is the most conceptually straightforward. However, even then the gene therapy agent may not equally reduce symptoms in patients with the same disease caused by different mutations, and even the samemutationcan be associated with different degrees of disease severity. Gene therapists often screen their patients to determine the type of mutation causing the disease before enrollment into a clinical trial.

The mutated gene may cause symptoms in more than one cell type. Cystic fibrosis, for example, affects lung cells and the digestive tract, so the gene therapy agent may need to replace the defective gene or compensate for its consequences in more than one tissue for maximum benefit. Alternatively, cell therapy can utilizestem cellswith the potential to mature into the multiple cell types to replace defective cells in different tissues.

In diseases like muscular dystrophy, for example, the high number of cells in muscles throughout the body that need to be corrected in order to substantially improve the symptoms makes delivery of genes and cells a challenging problem.

Some diseases, like cancer, are caused by mutations in multiple genes. Although different types of cancers have some common mutations, every tumor from a single type of cancer does not contain the same mutations. This phenomenon complicates the choice of a single gene therapy tactic and has led to the use of combination therapies and cell elimination strategies. For more information on gene and cell therapy strategies to treat cancer, please refer to the Cancer and Immunotherapy summary in the Disease Treatment section.

Disease models in animals do not completely mimic the human diseases and viralvectorsmay infect various species differently. The testing of vectors in animal models often resemble the responses obtained in humans, but the larger size of humans in comparison to rodents presents additional challenges in the efficiency of delivery and penetration of tissue.Gene therapy, cell therapy, and oligonucleotide-based therapy agents are often tested in larger animal models, including rabbit, dog, pig and nonhuman primate models. Testing human cell therapy in animal models is complicated by immune rejections. Furthermore, humans are a very heterogeneous population. Their immune responses to the vectors, altered cells, or cell therapy products may differ or be similar to results obtained in animal models.

Challenges in the development of gene and cell therapy agents: Scientific challenges include the development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. There are a lot of issues in that once sentence, and while these issues are easy to state, each one requires extensive research to identify the best means of delivery, how to control sufficient levels or numbers of cells, and factors that influence duration of gene expression or cell survival. After the delivery modalities are determined, identification and engineering of a promoter and control elements (on/off switch and dimmer switch) that will produce the appropriate amount of protein in the target cell can be combined with the relevant gene. This gene cassette is engineered into a vector or introduced into thegenomeof a cell and the properties of the delivery vehicle are tested in different types of cells in tissue culture. Sometimes things go as planned and then studies can be moved onto examination in animal models. In most cases, the gene/cell therapy agent may need to be improved further by adding new control elements to obtain the desired responses in cells and animal models.

Furthermore, the response of the immune system needs to be considered based on the type of gene or cell therapy being undertaken. For example, in gene or cell therapy for cancer, one aim is to selectively boost the existing immune response to cancer cells. In contrast, to treat genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted as an addition to the patients immune system.

If the new gene is inserted into the patients cellularDNA, the intrinsic sequences surrounding the new gene can affect its expression and vice versa. Scientists are now examining short DNA segments that may insulate the new gene from surrounding control elements. Theoretically, these insulator sequences would also reduce the effect of vector control signals in the gene cassette on adjacent cellular genes. Studies are also focusing on means to target insertion of the new gene into safe areas of the genome, to avoid influence on surrounding genes and to reduce the risk of insertional mutagenesis.

Challenges of cell therapy include the harvesting of the appropriate cell populations and expansion or isolation of sufficient cells for one or multiple patients. Cell harvesting may require specific media to maintain the stem cells ability toself-renew and mature into the appropriate cells. Ideally extra cells are taken from the individual receiving therapy. Those additional cells can expand in culture and can be induced to becomepluripotent stem cells(iPS), thus allowing them to assume a wide variety of cell types and avoiding immune rejection by the patient. The long term benefit of stem cell administration requires that the cells be introduced into the correct target tissue and become established functioning cells within the tissue. Several approaches are being investigated to increase the number of stem cells that become established in the relevant tissue.

Another challenge is developing methods that allow manipulation of the stem cells outside the body while maintaining the ability of those cells to produce more cells that mature into the desired specialized cell type. They need to provide the correct number of specialized cells and maintain their normal control of growth and cell division, otherwise there is the risk that these new cells may grow into tumors.

Challenges in funding: In most fields, funding for basic or applied research for gene and cell therapy is available through the National Institutes of Health (NIH) and private foundations. These are usually sufficient to cover the preclinical studies that suggest a potential benefit from a particular gene and cell therapy. Moving into clinical trials remains a huge challenge as it requires additional funding for manufacturing of clinical grade reagents, formal toxicology studies in animals, preparation of extensive regulatory documents, and costs of clinical trials.Biotechnology companies and the NIH are trying to meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

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The benefits and risks of stem cell technology – PMC

Stem cell technology will transform medical practice. While stem cell research has already elucidated many basic disease mechanisms, the promise of stem cellbased therapies remains largely unrealized. In this review, we begin with an overview of different stem cell types. Next, we review the progress in using stem cells for regenerative therapy. Last, we discuss the risks associated with stem cellbased therapies.

There are three major types of stem cells as follows: adult stem cells (also called tissue-specific stem cells), embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells.

A majority of adult stem cells are lineage-restricted cells that often reside within niches of their tissue of origin. Adult stem cells are characterized by their capacity for self-renewal and differentiation into tissue-specific cell types. Many adult tissues contain stem cells including skin, muscle, intestine, and bone marrow (Gan et al, 1997; Artlett et al, 1998; Matsuoka et al, 2001; Coulombel, 2004; Humphries et al, 2011). However, it remains unclear whether all adult organs contain stem cells. Adult stem cells are quiescent but can be induced to replicate and differentiate after tissue injury to replace cells that have died. The process by which this occurs is poorly understood. Importantly, adult stem cells are exquisitely tissue-specific in that they can only differentiate into the mature cell type of the organ within which they reside (Rinkevich et al, 2011).

Thus far, there are few accepted adult stem cellbased therapies. Hematopoietic stem cells (HSCs) can be used after myeloablation to repopulate the bone marrow in patients with hematologic disorders, potentially curing the underlying disorder (Meletis and Terpos, 2009; Terwey et al, 2009; Casper et al, 2010; Hill and Copelan, 2010; Hoff and Bruch-Gerharz, 2010; de Witte et al, 2010). HSCs are found most abundantly in the bone marrow, but can also be harvested at birth from umbilical cord blood (Broxmeyer et al, 1989). Similar to the HSCs harvested from bone marrow, cord blood stem cells are tissue-specific and can only be used to reconstitute the hematopoietic system (Forraz et al, 2002; McGuckin et al, 2003; McGuckin and Forraz, 2008). In addition to HSCs, limbal stem cells have been used for corneal replacement (Rama et al, 2010).

Mesenchymal stem cells (MSCs) are a subset of adult stem cells that may be particularly useful for stem cellbased therapies for three reasons. First, MSCs have been isolated from a variety of mesenchymal tissues, including bone marrow, muscle, circulating blood, blood vessels, and fat, thus making them abundant and readily available (Deans and Moseley, 2000; Zhang et al, 2009; Lue et al, 2010; Portmann-Lanz et al, 2010). Second, MSCs can differentiate into a wide array of cell types, including osteoblasts, chondrocytes, and adipocytes (Pittenger et al, 1999). This suggests that MSCs may have broader therapeutic applications compared to other adult stem cells. Third, MSCs exert potent paracrine effects enhancing the ability of injured tissue to repair itself. In fact, animal studies suggest that this may be the predominant mechanism by which MSCs promote tissue repair. The paracrine effects of MSC-based therapy have been shown to aid in angiogenic, antiapoptotic, and immunomodulatory processes. For instance, MSCs in culture secrete hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) (Nagaya et al, 2005). In a rat model of myocardial ischemia, injection of human bone marrow-derived stem cells upregulated cardiac expression of VEGF, HGF, bFGF, angiopoietin-1 and angiopoietin-2, and PDGF (Yoon et al, 2005). In swine, injection of bone marrow-derived mononuclear cells into ischemic myocardium was shown to increase the expression of VEGF, enhance angiogenesis, and improve cardiac performance (Tse et al, 2007). Bone marrow-derived stem cells have also been used in a number of small clinical trials with conflicting results. In the largest of these trials (REPAIR-AMI), 204 patients with acute myocardial infarction were randomized to receive bone marrow-derived progenitor cells vs placebo 37 days after reperfusion. After 4 months, the patients that were infused with stem cells showed improvement in left ventricular function compared to control patients. At 1 year, the combined endpoint of recurrent ischemia, revascularization, or death was decreased in the group treated with stem cells (Schachinger et al, 2006).

Embryonic stem cells are derived from the inner cell mass of the developing embryo during the blastocyst stage (Thomson et al, 1998). In contrast to adult stem cells, ES cells are pluripotent and can theoretically give rise to any cell type if exposed to the proper stimuli. Thus, ES cells possess a greater therapeutic potential than adult stem cells. However, four major obstacles exist to implementing ES cells therapeutically. First, directing ES cells to differentiate into a particular cell type has proven to be challenging. Second, ES cells can potentially transform into cancerous tissue. Third, after transplantation, immunological mismatch can occur resulting in host rejection. Fourth, harvesting cells from a potentially viable embryo raises ethical concerns. At the time of this publication, there are only two ongoing clinical trials utilizing human ES-derived cells. One trial is a safety study for the use of human ES-derived oligodendrocyte precursors in patients with paraplegia (Genron based in Menlo Park, California). The other is using human ES-derived retinal pigmented epithelial cells to treat blindness resulting from macular degeneration (Advanced Cell Technology, Santa Monica, CA, USA).

In stem cell research, the most exciting recent advancement has been the development of iPS cell technology. In 2006, the laboratory of Shinya Yamanaka at the Gladstone Institute was the first to reprogram adult mouse fibroblasts into an embryonic-like cell, or iPS cell, by overexpression of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 under ES cell culture conditions (Takahashi and Yamanaka, 2006). Yamakana's pioneering work in cellular reprogramming using adult mouse cells set the foundation for the successful creation of iPS cells from adult human cells by both his team (Takahashi et al, 2007) and a group led by James Thomson at the University of Wisconsin (Yu et al, 2007). These initial proof of concept studies were expanded upon by leading scientists such as George Daley, who created the first library of disease-specific iPS cell lines (Park et al, 2008). These seminal discoveries in the cellular reprogramming of adult cells invigorated the stem cell field and created a niche for a new avenue of stem cell research based on iPS cells and their derivatives. Since the first publication on cellular reprogramming in 2006, there has been an exponential growth in the number of publications on iPS cells.

Similar to ES cells, iPS cells are pluripotent and, thus, have tremendous therapeutic potential. As of yet, there are no clinical trials using iPS cells. However, iPS cells are already powerful tools for modeling disease processes. Prior to iPS cell technology, in vitro cell culture disease models were limited to those cell types that could be harvested from the patient without harm usually dermal fibroblasts from skin biopsies. However, mature dermal fibroblasts alone cannot recapitulate complicated disease processes involving multiple cell types. Using iPS technology, dermal fibroblasts can be de-differentiated into iPS cells. Subsequently, the iPS cells can be directed to differentiate into the cell type most beneficial for modeling a particular disease process. Advances in the production of iPS cells have found that the earliest pluripotent stage of the derivation process can be eliminated under certain circumstances. For instance, dermal fibroblasts have been directly differentiated into dopaminergic neurons by viral co-transduction of forebrain transcriptional regulators (Brn2, Myt1l, Zic1, Olig2, and Ascl1) in the presence of media containing neuronal survival factors [brain-derived neurotrophic factor, neurotrophin-3 (NT3), and glial-conditioned media] (Qiang et al, 2011). Additionally, dermal fibroblasts have been directly differentiated into cardiomyocyte-like cells using the transcription factors Gata4, Mef2c, and Tb5 (Ieda et al, 2010). Regardless of the derivation process, once the cell type of interest is generated, the phenotype central to the disease process can be readily studied. In addition, compounds can be screened for therapeutic benefit and environmental toxins can be screened as potential contributors to the disease. Thus far, iPS cells have generated valuable in vitro models for many neurodegenerative (including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis), hematologic (including Fanconi's anemia and dyskeratosis congenital), and cardiac disorders (most notably the long QT syndrome) (Park et al, 2008). iPS cells from patients with the long QT syndrome are particularly interesting as they may provide an excellent platform for rapidly screening drugs for a common, lethal side effect (Zwi et al, 2009; Malan et al, 2011; Tiscornia et al, 2011). The development of patient-specific iPS cells for in vitro disease modeling will determine the potential for these cells to differentiate into desired cell lineages, serve as models for investigating the mechanisms underlying disease pathophysiology, and serve as tools for future preclinical drug screening and toxicology studies.

Despite substantial improvements in therapy, cardiovascular disease remains the leading cause of death in the industrialized world. Therefore, there is a particular interest in cardiovascular regenerative therapies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes) (Codina et al, 2010). It is unclear whether the heart contains resident stem cells. However, experiments show that bone marrow mononuclear cells (BMCs) can repair myocardial damage, reduce left ventricular remodeling, and improve heart function by myocardial regeneration (Hakuno et al, 2002; Amado et al, 2005; Dai et al, 2005; Schneider et al, 2008). The regenerative capacity of human heart tissue was further supported by the detection of the renewal of human cardiomyocytes (1% annually at the age of 25) by analysis of carbon-14 integration into human cardiomyocyte DNA (Bergmann et al, 2009). It is not clear whether cardiomyocyte renewal is derived from resident adult stem cells, cardiomyocyte duplication, or homing of non-myocardial progenitor cells. Bone marrow cells home to the injured myocardium as shown by Y chromosome-positive BMCs in female recipients (Deb et al, 2003). On the basis of these promising results, clinical trials in patients with ischemic heart disease have been initiated primarily using bone marrow-derived cells. However, these small trials have shown controversial results. This is likely due to a lack of standardization for cell harvesting and delivery procedures. This highlights the need for a better understanding of the basic mechanisms underlying stem cell isolation and homing prior to clinical implementation.

Although stem cells have the capacity to differentiate into neurons, oligodendrocytes, and astrocytes, novel clinical stem cellbased therapies for central and peripheral nervous system diseases have yet to be realized. It is widely hoped that transplantation of stem cells will provide effective therapy for Parkinson's disease, Alzheimer's disease, Huntington's Disease, amyloid lateral sclerosis, spinal cord injury, and stroke. Several encouraging animal studies have shown that stem cells can rescue some degree of neurological function after injury (Daniela et al, 2007; Hu et al, 2010; Shimada and Spees, 2011). Currently, a number of clinical trials have been performed and are ongoing.

Dental stem cells could potentially repair damaged tooth tissues such as dentin, periodontal ligament, and dental pulp (Gronthos et al, 2002; Ohazama et al, 2004; Jo et al, 2007; Ikeda et al, 2009; Balic et al, 2010; Volponi et al, 2010). Moreover, as the behavior of dental stem cells is similar to MSCs, dental stem cells could also be used to facilitate the repair of non-dental tissues such as bone and nerves (Huang et al, 2009; Takahashi et al, 2010). Several populations of cells with stem cell properties have been isolated from different parts of the tooth. These include cells from the pulp of both exfoliated (children's) and adult teeth, the periodontal ligament that links the tooth root with the bone, the tips of developing roots, and the tissue that surrounds the unerupted tooth (dental follicle) (Bluteau et al, 2008). These cells probably share a common lineage from neural crest cells, and all have generic mesenchymal stem cell-like properties, including expression of marker genes and differentiation into mesenchymal cells in vitro and in vivo (Bluteau et al, 2008). different cell populations do, however, differ in certain aspects of their growth rate in culture, marker gene expression, and cell differentiation. However, the extent to which these differences can be attributed to tissue of origin, function, or culture conditions remains unclear.

There are several issues determining the long-term outcome of stem cellbased therapies, including improvements in the survival, engraftment, proliferation, and regeneration of transplanted cells. The genomic and epigenetic integrity of cell lines that have been manipulated in vitro prior to transplantation play a pivotal role in the survival and clinical benefit of stem cell therapy. Although stem cells possess extensive replicative capacity, immune rejection of donor cells by the host immune system post-transplantation is a primary concern (Negro et al, 2012). Recent studies have shown that the majority of donor cell death occurs in the first hours to days after transplantation, which limits the efficacy and therapeutic potential of stem cellbased therapies (Robey et al, 2008).

Although mouse and human ES cells have traditionally been classified as being immune privileged, a recent study used in vivo, whole-animal, live cell-tracing techniques to demonstrate that human ES cells are rapidly rejected following transplantation into immunocompetent mice (Swijnenburg et al, 2008). Treatment of ES cell-derived vascular progenitor cells with inter-feron (to upregulate major histocompatibility complex (MHC) class I expression) or in vivo ablation of natural killer (NK) cells led to enhanced progenitor cell survival after transplantation into a syngeneic murine ischemic hindlimb model. This suggests that MHC class I-dependent, NK cell-mediated elimination is a major determinant of graft survivability (Ma et al, 2010). Given the risk of rejection, it is likely that initial therapeutic attempts using either ES or iPS cells will require adjunctive immunosuppressive therapy. Immunosuppressive therapy, however, puts the patient at risk of infection as well as drug-specific adverse reactions. As such, determining the mechanisms regulating donor graft tolerance by the host will be crucial for advancing the clinical application of stem cellbased therapies.

An alternative strategy to avoid immune rejection could employ so-called gene editing. Using this technique, the stem cell genome is manipulated ex vivo to correct the underlying genetic defect prior to transplantation. Additionally, stem cell immunologic markers could be manipulated to evade the host immune response. Two recent papers offer alternative methods for gene editing. Soldner et al (2011) used zinc finger nuclease to correct the genetic defect in iPS cells from patients with Parkinson's disease because of a mutation in the -Synuclein (-SYN) gene. Liu et al (2011) used helper-dependent adenoviral vectors (HDAdV) to correct the mutation in the Lamin A (LMNA) gene in iPS cells derived from patients with HutchinsonGilford Progeria (HGP), a syndrome of premature aging. Cells from patients with HGP have dysmorphic nuclei and increased levels of progerin protein. The cellular phenotype is especially pronounced in mature, differentiated cells. Using highly efficient helper-dependent adenoviral vectors containing wild-type sequences, they were able to use homologous recombination to correct two different Lamin A mutations. After genetic correction, the diseased cellular phenotype was reversed even after differentiation into mature smooth muscle cells. In addition to the potential therapeutic benefit, gene editing could generate appropriate controls for in vitro studies.

Finally, there are multiple safety and toxicity concerns regarding the transplantation, engraftment, and long-term survival of stem cells. Donor stem cells that manage to escape immune rejection may later become oncogenic because of their unlimited capacity to replicate (Amariglio et al, 2009). Thus, ES and iPS cells may need to be directed into a more mature cell type prior to transplantation to minimize this risk. Additionally, generation of ES and iPS cells harboring an inducible kill-switch may prevent uncontrolled growth of these cells and/or their derivatives. In two ongoing human trials with ES cells, both companies have provided evidence from animal studies that these cells will not form teratomas. However, this issue has not been thoroughly examined, and enrolled patients will need to be monitored closely for this potentially lethal side effect.

In addition to the previously mentioned technical issues, the use of ES cells raises social and ethical concerns. In the past, these concerns have limited federal funding and thwarted the progress of this very important research. Because funding limitations may be reinstituted in the future, ES cell technology is being less aggressively pursued and young researchers are shying away from the field.

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The benefits and risks of stem cell technology - PMC

Sernova and Evotec Enter into an Exclusive Global Strategic Partnership for iPSC-Based Beta Cell Replacement Therapy to Develop and Commercialize a…

LONDON, Ontario, May 17, 2022 (GLOBE NEWSWIRE) -- Sernova Corp. (TSX-V:SVA)(SEOVF, Financial)(FSE/XETRA:PSH), a clinical-stage company and leader in regenerative medicine cell therapeutics, and Evotec SE (FSE: EVT; EVO), a global pharmaceutical and life science company, and leading developer of iPSC cell technologies for therapeutic applications, are pleased to announce an exclusive global strategic partnership to develop a best-in-class cell therapy treatment for people living with insulin-dependent diabetes. The two Companies will combine and leverage their respective technologies and scientific expertise to develop an implantable iPSC-based (induced pluripotent stem cells) beta cell replacement therapy to provide an unlimited insulin-producing cell source to treat patients with insulin-dependent diabetes.

The collaboration agreement is a transformative partnership that combines Sernovas Cell Pouch System technologies, which has demonstrated Phase 1/2 clinical proof-of-concept using human donor islets, with Evotecs iPSC-based beta cells. Incorporating Evotecs insulin-producing, ethically-derived beta cells within Sernovas Cell Pouch platform creates the potential to provide a functional cure for millions of people suffering from diabetes using a cGMP controlled and scalable off-the-shelf product.

With its long-standing beta cell development program, Evotec has demonstrated the ability to reliably produce an unlimited supply of high quality, stable, human iPSC-derived beta cells using its proprietary process for producing islet-like clusters in a quality-controlled scalable bioreactor process. These islet-like clusters have now been proven to be functionally equivalent to primary human islets in their ability to normalize blood glucose using in vivo models of type 1 diabetes (T1D).

The partnership provides Sernova a global exclusive option to license Evotecs iPSC-based beta cells for use in treating both type 1 and type 2 diabetes. In addition to entering into the collaboration agreement, Evotec has made a strategic equity investment of 15M and will make a further investment of 5M. Specifically, concurrently with the entering into the collaboration agreement, Evotec acquired a total of 12,944,904 common shares at a price of CAD $1.57 per share for gross proceeds to Sernova of $20,323,500. In addition, pursuant to an unconditional purchase warrant, Evotec will acquire, on or before August 31, 2022, a further 2,709,800 common shares at a price of CAD$2.50 per share for gross proceeds of $6,774,500. All of the securities issued to Evotec are subject to a four month hold period.

Further to the collaboration and Evotecs strategic equity investment, Dr. Cord Dohrmann, Chief Scientific Officer of Evotec will join Sernovas Board of Directors.

Dr. Philip Toleikis, President, and Chief Executive Officer of Sernova, commented, In tandem with our current clinical islet cell program, Sernova entered into multiple pharmaceutical research collaborations to identify the highest quality and most compatible iPSC cell technology, and validate the cells preclinically within our Cell Pouch System. Evotec is an iPSC powerhouse having dedicated many years and substantial resources to developing high quality and stable stem cell technologies for multiple therapeutic applications. In every sense, both as a global strategic partner and as an iPSC expert, Evotec has exceeded all our expectations and Dr. Dohrmanns appointment to Sernovas Board adds significant regenerative medicine depth and cell therapy expertise. Todays announcement of this joint iPSC beta-cell partnership completes the three pillars of our diabetes cell therapy platform. Alongside our clinically validated Cell Pouch System and recently acquired conformal coating immune protection technology, this now establishes a total regenerative medicine cell therapy solution for insulin-dependent diabetes.

Dr. Cord Dohrmann, Chief Scientific Officer of Evotec, commented, We searched long and hard for the right partner. Sernova clearly ticks all boxes with their clinically validated Cell Pouch technology, which fits perfectly to Evotecs iPSC-based beta cells. Together we will progress a highly differentiated first-in-class beta cell therapy into clinical development with the common goal to bring a truly transformative therapy to insulin-dependent diabetic patients. The synergies of Evotecs and Sernovas technologies puts Sernova in position to become the worlds leader in beta cell replacement therapy. Our equity investment underlines our strategic interest in this collaboration with Sernova. I am very much looking forward to collaborating with Sernova on the project as well as contributing to their Board of Directors.

Sernova has acquired an option for an exclusive global license to Evotecs Induced Pluripotent Stem Cell (iPSC)-based Beta cells to treat patients with insulin-dependent diabetes. From an operational perspective, the preclinical development program(s) will be jointly funded by Sernova and Evotec until IND acceptance. Sernova has the right to exercise its option for an exclusive global license upon IND filing. Evotec will contribute its cell manufacturing capabilities through research, development and product commercialization and will decide in the future on the joint funding of clinical development. Upon commercialization, there will be a profit-sharing arrangement between the two companies, with the split being dependent on Evotecs participation in funding the clinical development program.

Joint Sernova / Evotec Conference Call and Webcast Details:

Date: Tuesday, May 17, 2022Time: 8:30 am EDTUS Toll Free: 1-877-704-4453International: 1-201-389-0920Conference ID: 13730121Webcast: https://viavid.webcasts.com/starthere.jsp?ei=1550130&tp_key=3de87cce1d

A simultaneous slide presentation will be available via the above webcast link.

ABOUT SERNOVA CORP AND THE CELL POUCH SYSTEM CELL THERAPY PLATFORM

Sernova Corp is developing regenerative medicine therapeutic technologies using a medical device and immune protected therapeutic cells (i.e., human donor cells, corrected human cells and stem-cell derived cells) to improve the treatment and quality of life of people with chronic metabolic diseases such as insulin- dependent diabetes, blood disorders including hemophilia, and other diseases treated through replacement of proteins or hormones missing or in short supply within the body.

The Cell Pouch, as part of the Cell Pouch System, is a proprietary, scalable, implantable macro- encapsulation device solution designed for the long-term survival and function of therapeutic cells. After implantation, the device incorporates with tissue, forming highly vascularized, native tissue chambers for the transplantation and function of therapeutic cells, that release proteins and hormones as required to treat disease.

The Cell Pouch, along with therapeutic cells, has been shown to provide long-term safety and efficacy in small and large animal models of diabetes and has been proven to provide a biologically compatible environment for insulin-producing cells in humans in a Canadian first-in-human study. Sernova is currently conducting a Phase 1/2 clinical trial study at the University of Chicago. Encouraging interim results have been presented at several international scientific conferences.

For more information, please visit http://www.sernova.com

ABOUT EVOTEC AND iPSC

Induced 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. The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells. He was awarded the 2012 Nobel Prize along with Sir John Gurdon for the discovery that mature cells can be reprogrammed to become pluripotent. 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. Evotecs 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 Companys proprietary EVOcells platform.

For further information contact:

Corporate and Investors:Sernova CorpChristopher Barnes Tel: (519) 858-5126 [emailprotected] http://www.sernova.com

Investors:Corey Davis, Ph.D. LifeSci Advisors, LLC [emailprotected] Tel: 212-915-2577

Media: Elizabeth Miller, MDLifeSci Communications[emailprotected]

FORWARD-LOOKING INFORMATION

This release may contain forward-looking statements. Forward-looking statements are statements that are not historical facts and are generally, but not always, identified by the words expects, plans, anticipates, believes, intends, estimates, projects, potential and similar expressions, or that events or conditions will, would, may, could or should occur. Although Sernova believes the expectations expressed in such forward-looking statements are based on reasonable assumptions, such statements are not guarantees of future performance, and actual results may differ materially from those in forward-looking statements. Forward-looking statements are based on the beliefs, estimates, and opinions of Sernovas management on the date such statements were made, which include our beliefs about the conduct and outcome of clinical trials, and the development of new technologies, cell therapy solutions and or products. The information disclosed represents results from one patient and may not be representative of all study patients or of the final study results. Sernova expressly disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise.

Original post:
Sernova and Evotec Enter into an Exclusive Global Strategic Partnership for iPSC-Based Beta Cell Replacement Therapy to Develop and Commercialize a...

Rising Focus on Exploring Potential of Stem Cells as Therapeutic Tools in Drug Targeting and Regenerative Medicine to Fuel Revenue Growth of Stem…

NEW YORK, Jan. 10, 2022 /PRNewswire/ --Reports and Data has published its latest report titled "Stem Cells Market By Product (Adult Stem Cells, Human Embryonic Stem Cells, IPS Cells, and Very Small Embryonic-Like Stem Cells), By Technology (Cell Acquisition, Cell Production, Cryopreservation, and Expansion & Sub-Culture), By Therapies (Allogeneic Stem Cell Therapy and Autologous Stem Cell Therapy), and By Application (Regenerative Medicine and Drug Discovery & Discovery), and By Region Forecast To 2028."

According to the latest report by Reports and Data, the global stem cells market size was USD 10.13 billion in 2020 and is expected to reach USD 19.31 Billion in 2028 and register a revenue CAGR of 8.4% during the forecast period, 2021-2028.

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Drivers, Restraints, & Opportunities

Stem cells are cells that have the potential to differentiate into different types of cells in the body. Stem cells have the ability of self-renewal and differential into specialized adult cell types. Stems cells are being explored for their potential in tissue regeneration and repair and in treatment of chronic diseases. Increasing number of clinical trials are underway to assess and establish safety and efficacy of stem cell therapy for various diseases and disorders. Rapid advancement in stem cell research, rising investment to accelerate stem cell therapy development, and increasing use of stem cells as therapeutic tools for treatment of neurological diseases and malignancies are some key factors expected to drive market revenue growth over the forecast period. in addition, growing incidence of type 1 diabetes, spinal cord injuries, Parkinson's diseases, and Alzheimer's disease, among others have further boosted adoption of stem cell therapies and is expected to fuel revenue growth of the market going ahead.

Stem cells are basic cells in the body from which cells with specialized functions are generated such as heart muscle cells, brain cells, bone cells, or blood cells. Maturation of stem cells into specialized cells have enabled researchers and doctors better understand the pathophysiology of diseases and conditions. Stem cells have great potential to be grown to become new tissues for transplant and in regenerative medicine. Stem cells that are programmed to differentiate into tissue-specific cells are widely being used to test new drugs that target specific diseases, such as nerve cells can be generated to test safety and efficacy of drugs that are being developed for nerve disorders and diseases. Stem cells are of two major types: pluripotent cells that can differentiate into any cells in the adult body and multipotent cells that are restricted to differentiate into limited population of cells. Increasing clinical research is being carried out to advance stem cell therapy to improve cardiac function and to treat muscular dystrophy and heart failure. Recent progress in preclinical and clinical research have expanded application scope of stem cell therapy into treating diseases for which currently available therapies have failed to be effective. This is expected to continue to drive revenue growth of the market going ahead.

However, immunity-related concerns associated with stem cell therapies, increasing incidence of abnormalities in adult stem cells, and rising number of ethical issues associated with stem cell research such as risk of harm during isolation of stem cells, therapeutic misconception, and concerns surrounding safety and efficacy of stem cell therapies are some key factors expected to restrain market growth to a certain extent over the forecast period.

To identify the key trends in the industry, research study at https://www.reportsanddata.com/report-detail/stem-cells-market

COVID-19 Impact Analysis

Rising use of Human Embryonic Stem Cells in Regenerative Medicine to Drive Market Growth:

Human embryonic stem cells (ESCs) segment is expected to register significant revenue growth over the forecast period attributable to increasing use of human embryonic stem cells in regenerative medicine and tissue repair, rising application in drug discovery, and growing importance of embryonic stem cells as in vitro models for drug testing.

Cryopreservation Segment to Account for Largest Revenue Share:

Cryopreservation segment is expected to dominate other technology segments in terms of revenue share over the forecast period. Cryopreservation techniques are widely used in stem cell preservation and transport owing to its ability to provide secure, stable, and extended cell storage for isolated cell preparations. Cryopreservation also provides various benefits to cell banks and have numerous advantages such as secure storage, flexibility and timely delivery, and low cost and low product wastage.

Regenerative Medicine Segment to Lead in Terms of Revenue Growth:

Regenerative medicine segment is expected to register robust revenue CAGR over the forecast period attributable to significant progress in regenerative medicine, increasing research and development activities to expand potential of stem cell therapy in treatment of wide range of diseases such as neurodegenerative diseases, diabetes, and cancers, among others, and rapid advancement in cell-based regenerative medicine.

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North America to Dominate Other Regions in Terms of Revenue Share:

North America is expected to dominate other regional markets in terms of revenue share over the forecast period attributable to increasing adoption of stem cell therapy to treat chronic diseases, rising investment to accelerate stem cell research, approval for clinical trials and research studies, growing R&D activities to develop advanced cell-based therapeutics, and presence of major biotechnology and pharmaceutical companies in the region.

Asia Pacific Market Revenue to Expand Significantly:

Asia Pacific is expected to register fastest revenue CAGR over the forecast period attributable to increasing R&D activities to advance stem cell-based therapies owing to rapidly rising prevalence of chronic diseases such as cancer and diabetes, rising investment to accelerate development of state-of-the-art healthcare and research facilities, establishment of a network of cell banks, increasing approval for regenerative medicine clinical trials, and rising awareness about the importance of stem cell therapies in the region.

Major Companies in the Market Include:

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Market Segmentation:

For the purpose of this report, Reports and Data has segmented the stem cells market based on product, technology, therapies, application, and region:

Product Outlook (Revenue, USD Billion; 2018-2028)

Technology Outlook (Revenue, USD Billion; 2018-2028)

Therapy Outlook (Revenue, USD Billion; 2018-2028)

Application Outlook (Revenue, USD Billion; 2018-2028)

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Regional Outlook (Revenue, USD Billion, 2018-2028)

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Rising Focus on Exploring Potential of Stem Cells as Therapeutic Tools in Drug Targeting and Regenerative Medicine to Fuel Revenue Growth of Stem...

SC21- 21st century cellular medicines specialists – The Thaiger

Sponsored Article

Although stem cells are known to work wonders, there is still a lot of misunderstanding about what they are, what they do, and how they work.

The good news is that StemCells21 can clear everything up for you. SC21 produces all of its cellular medications in-house, and all of its treatments are performed at its cutting-edge medical centre in Bangkok. Its a one-stop shop that adheres to high-quality standards.

This company will be on display at the Thailand International Boat Show, which will be hosted at Royal Phuket Marina from January 6 to 9 next year. Staff from StemCells21 will be on hand to walk you through the producers, pricing, and techniques.

StemCells21s laboratory is a full-scale culture & analysis laboratory specialising in the production & treatment of Mesenchymal Stem Cells (StemCells21), and Natural Killer Cells (ImmuneCells21). It has also launched a new generation of regenerative medicine called Pluripotent Stem Cells (iPSC21), which hold great potential for impacting chronic diseases in the quest for anti-ageing.

The lab has seven scientists & stem cell researchers, a couple of who have worked with Professor Shinya Yamanaka, who was awarded the Nobel Prize in Physiology or Medicine in 2012 for the discovery that mature cells can be reprogrammed to become pluripotent (iPS cells).

Photo Via: Stemcells 21

Before StemCells21 was created, Managing Director Paul Collier and co-founder Sergei Dmitrievs experienced the power of stem cells either first hand or through the treatment of someone close to them. They knew that stem cells could deliver positive health results, and also knew stem cell treatmentsand the clinics that administered themhad room for improvement.

After deep laboratory investigation, they came to see that most clinics utilised relatively low-quality stem cells and incomplete treatments. While these clinics could deliver a certain level of positive results, they were only scratching the surface of the promise that stem cell treatments could deliver.

Furthermore, the clinics themselves frequently provided a less-than-ideal patient experience. Clinics were generally hectic, unprofessional, and unwelcoming. Patients were often administered a single treatment and sent on their way, unsure if they had experienced an efficacious treatment or if they had travelled and paid for nothing.

StemCells21 was created to offer superior results and give you a welcoming experience. It was set up to provide the global community with access to treatments that few people are aware of, and to offer health benefits that are superior to what most people ever imagined were possible.

The SC21 complex in Bangkok houses the StemCells21, ImmuneCells21, and IPS21 laboratories, as well as the premium 5* IntelliHealth+ (IH+) Clinic.

IntelliHealth+ is a state-of-the-art medical centre licensed by the Thai medical authorities. The luxurious design, efficient workflow layouts, and modern treatments make it the ideal choice for customers seeking a premium level of healthcare in 5* settings.

The centre treats patients from all over the world and has staff who speak fluent English, Arabic, Chinese, Russian, Thai and Spanish.

Furthermore, SC21s come from all corners of the globe for these cutting edge treatments. Many VIPs travel to the clinic including presidents, prime ministers, sports stars, football managers, bank owners and heads of major corporations, many of whom return every six to twelve months and have been doing so for years.

Recently, SC21 treated a ten-year-old British boy who had Ewing sarcoma develop in his arm, which then spread to other areas. He had tried every treatment option in the UK. His trip and treatment were sponsored by UK football teams and the public. Since he started treatment hes put on weight, hes vibrant, and his demeanour has totally changed. Various tests and scans have shown he is responding very well to the immunotherapy course and will perform another round in a few months time.

SC21 focuses on three main areas: anti-ageing and longevity; orthopaedic and muscular-skeletal issues (knee, hip, back & shoulder); and chronic diseases (diabetes, liver cirrhosis, lung, respiratory, hearing & vision disorders). Aside from that, the clinic can also help with chronic fatigue and burn-out syndrome.

Outpatient services for anti-ageing, immunotherapy and regenerative medicine are available at the centre. The anti-ageing clinic has a cutting-edge approach to skin rejuvenation, dermatology, detoxification, and wellbeing. A youthful appearance, more energy, improved mental capacity and mobility, reduced aches and pains, and a stronger immune system are among the benefits.

Photo Via: Stemcells 21

The high level of traditional medicine and the unique protocols designed by the IH+ teams give patients real therapeutic benefits and longevity.

According to Paul Collier, a client typically receives two sessions of stem cell injections during a treatment intravenous for systemic and local to the target and is required to stay in Bangkok for two days following their procedure to monitor any complications that may arise. Then theyre given a two-month take-home kit that comprises self-administered injections (similar to insulin) that target specific growth factors in organs or tissues that need to be repaired. These can also be taken orally, but they are less effective.

He goes on to say that stem cells are the foundation of the human body. They split over and over to produce humans from an embryo at the start of our lives. They restore cells in your blood, bone, skin, and organs throughout your life to keep you alive and functioning. Stem cells have two distinct properties that distinguish them from other types of cells in our bodies.

First, they can self-renew (mitosis), which is a stage of the cell cycle in which replicated chromosomes are divided into two new nuclei. As a result, identical duplicated cells are produced.

Secondly, they have the ability to differentiate into specialized cells such as cartilage, heart cells, liver cells, and neurons. No other cell in the body has the natural ability to generate new cell types.

Mesenchymal Stem Cells (MSCs) are at the core of StemCells21s regenerative programs. They are multipotent stem cells derived from various adult and fetal tissues. A large number of studies have shown the beneficial effects of MSC-based therapies to treat different pathologies, including neurological disorders, cardiac ischemia, diabetes, and bone and cartilage diseases.

StemCells21 also has arthritis treatment, which reduces inflammation & joint pain, increases cartilage growth, improves mobility & joint stability and lessens dependence on medication. The clinics degenerative spine treatments help discs regenerate and stabilize the spine.

On top of that, it provides lung & liver disease treatment as well as treatments for autism, cerebral palsy, diabetes, motor neuron disease, multiple sclerosis and immune disorders.

Theres even eye treatment, which reduces blurred vision & field of vision defects, improves night vision & enhances colour texture.

Photo Via: Stemcells 21

SC21 can even help with certain types of cancer by taking a clients blood and growing their natural killer cells (immunotherapy) over a 21-day period. Through various stimuli, their cytotoxicity is increased which kills cancer and virally-affected cells.

Paul says stem cell therapy should be looked at before undergoing any kind of invasive surgery. The type of medicine should certainly be an intervention before surgery. If you are looking at knee replacement, why not consider an injection of a biologic that would only take a couple of days and has the potential to remodel the cartilage, because once you perform surgery there is no going back.

SC21 also produces a wide range of stem-cell extract-based cosmetics and nutritional supplements, which are available at their medical centres and online under the brand SC21 Biotech.

The Thailand International Boat Show will feature Paul Collier and his team. Theyll be able to answer any of your questions about the cost, procedure, and treatment. On top of that, they will also assist you in educating yourself and managing your expectations so that you do not expect more than stem cell therapy can provide. If you want to get treatment, they will also provide you with a complete report on all treatments. SC21 is fully compliant with international regulations and guidelines.

http://www.stemcells21.com http://www.intellihealthplus.com

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SC21- 21st century cellular medicines specialists - The Thaiger

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)

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