Category Archives: Stem Cell Therapy

REDWOOD CITY, Calif., June 06, 2022 (GLOBE NEWSWIRE) -- Jasper Therapeutics, Inc. ( JSPR), a biotechnology company focused on hematopoietic cell transplant therapies, today announced that its 2022 Annual Meeting of Stockholders will be held on Thursday, June 23, 2022, at 10:00 a.m. Pacific Time. This years meeting is a virtual stockholder meeting conducted exclusively via live audio webcast on the Internet at https://www.cstproxy.com/JasperTherapeutics/2022. As described in the proxy materials previously distributed, stockholders of record at the close of business on April 26, 2022 are entitled to participate and vote at the 2022 Annual Meeting. To participate, stockholders will need to enter the 12-digit control number included in the proxy materials delivered to such stockholders.

Information about the virtual meeting webcast and instructions for how stockholders can participate in the 2022 Annual Meeting are included in the definitive proxy statement filed with the Securities and Exchange Commission on April 29, 2022 and are available on the InvestorsFinancials & Filings section of Jasper Therapeutics website at http://www.jaspertherapeutics.com or the website for the 2022 Annual Meeting at https://www.cstproxy.com/JasperTherapeutics/2022.

About Jasper Therapeutics, Inc.

Jasper Therapeutics, Inc. is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, an anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing hematopoietic cell transplantation. It is designed to enable safer and more effective, and potentially curative, allogeneic hematopoietic cell transplants and gene therapies. A clinical study of JSP191 as a novel, disease-modifying, therapeutic for patients with lower risk MDS is also planned to begin in 2022. In parallel, Jasper Therapeutics, Inc. is advancing its preclinical mRNA hematopoietic stem cell grafts platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

Contacts:

John Mullaly (investors)LifeSci Advisors617-429-3548[emailprotected]

Jeet Mahal (investors)Jasper Therapeutics650-549-1403[emailprotected]

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Jasper Therapeutics Announces Annual Virtual Stockholders Meeting to be Held on Thursday, June 23, 2022 - GuruFocus.com

Scientists have successfully developed a revolutionary cancer treatment that lights up and wipes out microscopic cancer cells, in a breakthrough that could enable surgeons to more effectively target and destroy the disease in patients.

A European team of engineers, physicists, neurosurgeons, biologists and immunologists from the UK, Poland and Sweden joined forces to design the new form of photoimmunotherapy.

Experts believe it is destined to become the worlds fifth major cancer treatment after surgery, chemotherapy, radiotherapy and immunotherapy.

The light-activated therapy forces cancer cells to glow in the dark, helping surgeons remove more of the tumours compared with existing techniques and then kills off remaining cells within minutes once the surgery is complete. In a world-first trial in mice with glioblastoma, one of the most common and aggressive types of brain cancer, scans revealed the novel treatment lit up even the tiniest cancer cells to help surgeons remove them and then wiped out those left over.

Trials of the new form of photoimmunotherapy, led by the Institute of Cancer Research, London, also showed the treatment triggered an immune response that could prime the immune system to target cancer cells in future, suggesting it could prevent glioblastoma coming back after surgery. Researchers are now also studying the new treatment for the childhood cancer neuroblastoma.

Brain cancers like glioblastoma can be hard to treat and, sadly, there are too few treatment options for patients, the study leader, Dr Gabriela Kramer-Marek, told the Guardian. Surgery is challenging due to the location of the tumours, and so new ways to see tumour cells to be removed during surgery, and to treat residual cancer cells that remain afterwards, could be of great benefit.

The ICRs team leader in preclinical molecular imaging added: Our study shows that a novel photoimmunotherapy treatment using a combination of a fluorescent marker, affibody protein and near-infrared light can both identify and treat leftover glioblastoma cells in mice. In the future, we hope this approach can be used to treat human glioblastoma and potentially other cancers, too.

The therapy combines a special fluorescent dye with a cancer-targeting compound. In the trial in mice, the combination was shown to dramatically improve the visibility of cancer cells during surgery and, when later activated by near-infrared light, to trigger an anti-tumour effect.

Scientists from the ICR, Imperial College London, the Medical University of Silesia, Poland, and the Swedish company AffibodyAB believe the novel treatment could help surgeons more easily and effectively remove particularly challenging tumours, such as those in the head and neck.

The joint effort was largely funded by the Cancer Research UK Convergence Science Centre at the ICR and Imperial College London a partnership that brings together international scientists from engineering, physical and life sciences specialisms to find innovative ways to tackle cancer.

Multidisciplinary working is critical to finding innovative solutions to address the challenges we face in cancer research, diagnosis and treatment and this study is a great example, said Prof Axel Behrens, the leader of the cancer stem cell team at the ICR and scientific director of the Cancer Research UK Convergence Science Centre.

This research demonstrates a novel approach to identifying and treating glioblastoma cells in the brain using light to turn an immunosuppressive environment into an immune-vulnerable one, and which has exciting potential as a therapy against this aggressive type of brain tumour.

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After decades of progress in treating cancer, the four main forms in existence today surgery, chemotherapy, radiotherapy and immunotherapy mean more people who are diagnosed with the disease can be treated effectively, and large numbers can live healthily for many years.

However, the close proximity of some tumours to vital organs in the body means it is vital new ways to treat cancer are developed so doctors can overcome the risk of harming healthy parts of the body. Experts believe that photoimmunotherapy could be the answer.

When tumours grow in sensitive areas of the brain such as the motor cortex, which is involved in the planning and control of voluntary movements, glioblastoma surgery can leave behind tumour cells that can be very hard to treat and which mean the disease can come back more aggressively later.

The new treatment uses synthetic molecules called affibodies. These are tiny proteins engineered in the lab to bind with a specific target with high precision, in this case a protein called EGFR which is mutated in many cases of glioblastoma.

The affibodies were then combined with a fluorescent molecule called IR700, and administered to the mice before surgery. Shining light on the compounds caused the dye to glow, highlighting microscopic regions of tumours in the brain for surgeons to remove. The laser then switched to near-infrared light, which triggered anti-tumour activity, killing the remaining cells after surgery.

Photoimmunotherapies could help us to target the cancer cells that cant be removed during surgery, which may help people live longer after their treatment, said Dr Charles Evans, the research information manager at Cancer Research UK. He cautioned that there were still technical challenges to overcome, such as reaching all parts of a tumour with near-infrared light, but added that he was excited to see how this research will develop.

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Scientists harness light therapy to target and kill cancer cells in world first - The Guardian

HONG KONG, June 17, 2022 /PRNewswire/ -- Global Cord Blood Corporation (NYSE: CO) ("GCBC" or the "Company"), China's leading provider of cord blood collection, laboratory testing, hematopoietic stem cell processing and stem cell storage services, is pleased to announce that Cellenkos, Inc. ("CLNK") recently announced that the U.S. Food and Drug Administration ("FDA") has cleared its Investigational New Drug ("IND") application to initiate a Phase1b, open-label study of CK0804 as an add on therapy to ruxolitinib in patients with myelofibrosis who experience a suboptimal response to ruxolitinib. Details related to this news can be found via the following Cellenkos news announcement:

Cellenkos Receives FDA Clearance of Investigational New Drug (IND) Application for CK0804 as Add on Therapy to Ruxolitinib for the Treatment of Myelofibrosis (prnewswire.com)

Ms. Ting Zheng, Chief Executive Officer and Chairperson of GCBC commented, "The Global Cord Blood team is encouraged by the above news announced by CLNK which highlights apotentially transformative treatment for myelofibrosis patients.We congratulate CLNK team on this development."

About Global Cord Blood Corporation

Global Cord Blood Corporation is an umbilical cord blood banking operator serving multiple regions in China. Global Cord Blood Corporation provides cord blood collection, laboratory testing, hematopoietic stem cell processing and stem cell storage services. For more information, please visit the Company's website at: http://www.globalcordbloodcorp.com.

For more information, please contact:

Global Cord Blood CorporationInvestor Relations DepartmentTel: (+852) 3605-8180Email: ir@globalcordbloodcorp.com

ICR, Inc.William ZimaTel: (+86) 10-6583-7511U.S. Tel: (646) 405-5185Email: William.zima@icrinc.com

Excerpt from:
Global Cord Blood Corporation Announced Cellenkos Receives FDA Clearance of IND Application for CK0804 as Add on Therapy to Ruxolitinib for the...

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Researchers hope stem cells will one day be effective in the treatment of many medical conditions and diseases. But unproven stem cell treatments can be unsafeso get all of the facts if youre considering any treatment.

Stem cells have been called everything from cure-alls to miracle treatments. But dont believe the hype. Some unscrupulous providers offer stem cell products that are both unapproved and unproven. So beware of potentially dangerous proceduresand confirm whats really being offered before you consider any treatment.

The facts: Stem cell therapies may offer the potential to treat diseases or conditions for which few treatments exist. Sometimes called the bodys master cells, stem cells are the cells that develop into blood, brain, bones, and all of the bodys organs. They have the potential to repair, restore, replace, and regenerate cells, and could possibly be used to treat many medical conditions and diseases.

But the U.S. Food and Drug Administration is concerned that some patients seeking cures and remedies are vulnerable to stem cell treatments that are illegal and potentially harmful. And the FDA is increasing its oversight and enforcement to protect people from dishonest and unscrupulous stem cell clinics, while continuing to encourage innovation so that the medical industry can properly harness the potential of stem cell products.

To do your part to stay safe, make sure that any stem cell treatment you are considering is either:

And see the boxed section below for more advice.

The FDA has the authority to regulate stem cell products in the United States.

Today, doctors routinely use stem cells that come from bone marrow or blood in transplant procedures to treat patients with cancer and disorders of the blood and immune system.

With limited exceptions, investigational products must also go through a thorough FDA review process as investigators prepare to determine the safety and effectiveness of products in well-controlled human studies, called clinical trials. The FDA has reviewed many stem cell products for use in these studies.

As part of the FDAs review, investigators must show how each product will be manufactured so the FDA can make sure appropriate steps are being taken to help assure the products safety, purity, and strength (potency). The FDA also requires sufficient data from animal studies to help evaluate any potential risks associated with product use. (You can learn more about clinical trials on the FDAs website.)

That said, some clinics may inappropriately advertise stem cell clinical trials without submitting an IND. Some clinics also may falsely advertise that FDA review and approval of the stem cell therapy is unnecessary. But when clinical trials are not conducted under an IND, it means that the FDA has not reviewed the experimental therapy to help make sure it is reasonably safe. So be cautious about these treatments.

About FDA-approved Products Derived from Stem Cells

The only stem cell-based products that are FDA-approved for use in the United States consist of blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood.

These products are approved for limited use in patients with disorders that affect the body system that is involved in the production of blood (called the hematopoietic system). These FDA-approved stem cell products are listed on the FDA website. Bone marrow also is used for these treatments but is generally not regulated by the FDA for this use.

All medical treatments have benefits and risks. But unproven stem cell therapies can be particularly unsafe.

For instance, attendees at a 2016 FDA public workshop discussed several cases of severe adverse events. One patient became blind due to an injection of stem cells into the eye. Another patient received a spinal cord injection that caused the growth of a spinal tumor.

Other potential safety concerns for unproven treatments include:

Note: Even if stem cells are your own cells, there are still safety risks such as those noted above. In addition, if cells are manipulated after removal, there is a risk of contamination of the cells.

When stem cell products are used in unapproved waysor when they are processed in ways that are more than minimally manipulated, which relates to the nature and degree of processingthe FDA may take (and has already taken) a variety of administrative and judicial actions, including criminal enforcement, depending on the violations involved.

In August 2017, the FDA announced increased enforcement of regulations and oversight of stem cell clinics. To learn more, see the statement from FDA Commissioner Scott Gottlieb, M.D., on the FDA website.

And in March 2017, to further clarify the benefits and risks of stem cell therapy, the FDA published a perspective article in the New England Journal of Medicine.

The FDA will continue to help with the development and licensing of new stem cell therapies where the scientific evidence supports the products safety and effectiveness.

Know that the FDA plays a role in stem cell treatment oversight. You may be told that because these are your cells, the FDA does not need to review or approve the treatment. That is not true.

Stem cell products have the potential to treat many medical conditions and diseases. But for almost all of these products, it is not yet known whether the product has any benefitor if the product is safe to use.

If you're considering treatment in the United States:

If you're considering treatment in another country:

Excerpt from:
FDA Warns About Stem Cell Therapies | FDA

Stem cell technology is a rapidly developing field that combines the efforts of cell biologists, geneticists, and clinicians and offers hope of effective treatment for a variety of malignant and non-malignant diseases. Stem cells are defined as totipotent progenitor cells capable of self renewal and multilineage differentiation.1 Stem cells survive well and show stable division in culture, making them ideal targets for in vitro manipulation. Although early research has focused on haematopoietic stem cells, stem cells have also been recognised in other sites. Research into solid tissue stem cells has not made the same progress as that on haematopoietic stem cells. This is due to the difficulty of reproducing the necessary and precise three dimensional arrangements and tight cell-cell and cell-extracellular matrix interactions that exist in solid organs. However, the ability of tissue stem cells to integrate into the tissue cytoarchitecture under the control of the host microenvironment and developmental cues, makes them ideal for cell replacement therapy. In this overview, we briefly discuss the current research and the clinical status of treatments based on haematopoietic and tissue stem cells.

Stem cells are progenitor cells that are capable of self renewal and differentiation into many different cell lineages

Stem cells have potential for treatment of many malignant and non-malignant diseases

Peripheral blood stem cells are used routinely in autologous and allogeneic bone marrow transplantation

Gene transfer into haematopoetic stem cells may allow treatment of genetic or acquired diseases

Embryonic stem cells may eventually be grown in vitro to produce complex organs

Neuronal stem cells are being used for neurone replacement in neurovegetative disorders such as Parkinson's and Huntingdon's diseases

Haematopoietic stem cells are a somatic cell population with highly specific homing properties and are capable of self renewal and differentiation into multiple cell lineages.2 Human haematopoietic progenitor cells, like stromal cell precursors in bone marrow, express the CD34 antigen, a transmembrane cell surface glycoprotein identified by the My10 monoclonal antibody.3 However, pluripotent stem cells constitute only a small fraction of the whole CD34+ population, which is by itself rather heterogeneous regarding phenotype and function. The best way to define haematopoietic stem cells is from their functional biology. They are known to restore multilineage, long term haematopoietic cell differentiation, and maturation in lethally cytoablated hosts.4 Haematopoietic stem cells can be obtained from bone marrow, peripheral blood,5 umbilical cord blood,6 and fetal liver.7

The use of peripheral blood stem cells in both autologous and allogeneic transplantation has become routine as they can be collected on an outpatient basis and also promote a consistent acceleration in haematopoietic reconstitution after engraftment.8 Umbilical cord blood stem cells have been used progressively in paediatric patients, from both related and unrelated HLA-matched donors. In recipients with severe T cell immunodeficiency disorders, fast engraftment is required together with a low risk of graft versus host disease and a low viral transmission rate.9 Since umbilical cord blood stem cells can be expanded in vitro or frozen for storage in cell banks10 they have been used in clinical trials for both autologous and allogeneic haematopoietic stem cell transplantation.11

The bone marrow is a mesenchyme derived tissue consisting of a complex haematopoietic cellular component supported by a microenvironment composed of stromal cells embedded in a complex extracellular matrix.12 This extracellular matrix has an important role in the facilitation of cell-to-cell interaction, in addition to a more complex role in the binding and presentation of cytokines to the haematopoietic progenitor cells.13 The cytokine milieu and extracellular matrix interaction provides the road map for maturation and differentiation of stem cells,14 which should be instrumental for their in vitro manipulation before therapeutic use. For example, haematopoietic stem cells can be manipulated in vitro to generate dendritic cells, the most potent antigen presenting cells.

Dendritic cells have a pivotal role in the elicitation and regulation of antigen specific, major histocompatibility complex-restricted T cell responses and are thought to be the only antigen presenting cells able to prime naive T cells. Dendritic cells can be derived from CD34+ precursors in response to granulocyte macrophage colony stimulating factor and tumour necrosis factor and from monocytes cultured with granulocyte macrophage colony stimulating factor and interleukin-4.15 In vitro generated dendritic cells (fig) that have been transduced with genes coding for tumour specific antigens or pulsed with tumour specific antigen or peptide could be useful for induction of cytotoxic T cell responses.16 Dendritic cell tumour vaccines could be important future therapeutic tools; phase II clinical trials are under way and show limited efficacy.17 On the other hand, the migration and function of dendritic cells derived from liver in an allogeneic environment may be seminal in the development of donor specific tolerance.1820 Genetic engineering of dendritic cells to express immunosuppressive or immunoregulatory molecules may provide a novel method to promote graft tolerance, reducing dependence on systemic immunosuppression.21

Haematopoietic stem cells themselves are also a promising target for gene therapy. Haematopoietic stem cells have been made resistant to one or more cytotoxic drugs22 with retroviral transfection of the multidrug resistance gene (MDR1). This should help circumvent the myelosuppressive effects of standard regimens of chemotherapy.23 Haematopoietic stem cells can also be genetically marked to allow assessment of patterns of cell survival, localisation, and function after bone marrow transplantation.24 This strategy has already been used with retroviral vectors.25 Double genetic marking is also being used to determine the long term effects of different protocols of cytokines given to promote bone marrow regeneration after cytoablative treatment.26 Gene transfer into haematopoietic stem cells represents a novel approach for treating some genetic or acquired diseases. So far, transduction of genes into humans using haematopoietic stem cells has shown low efficiency, especially in the quiescent stem cell population.27

Recent advances in reproductive biology and gene therapy have used ex vivo transduced autologous umbilical cord blood cells or direct targeting in utero as a potential means to correct haematopoietic, immunological, and metabolic single gene disorders.28 This technique has the advantage of using normal haematological development, which induces the fetus to allow space for a new cell population and promotes tolerance in the developing immune system. Unfortunately, infection and graft versus host disease are still potential risks for both the mother and the fetus. However, advances in the understanding of dose requirements and manipulation of peripheral blood sources to enrich for stem cells may provide strategies to overcome these problems.

The adult bone marrow also contains mesenchymal stem cells29 which are involved in the regeneration of mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, adipose tissue, and stroma. Although human mesenchymal stem cells have been isolated, it remains unclear how basal nutrients, cell density, spatial organisation, mechanical forces, growth factors, and cytokines control their differentiation.30 Isolated human mesenchymal stem cells constitute a single, phenotypically distinct population and are uniformly positive for SH2, SH3, CD44, CD71, CD90, CD106, CD120a, and CD124. They are also negative for CD14 and CD34 and can be induced to differentiate into adipocytes, chondrocytes, tenocytes, and osteocytes. Transplantation of mesenchymal stem cells into tendon defects in rabbits can significantly improve biomechanical properties of the damaged area.31

Embryonic stem cells were first isolated in 1981 through studies focusing primarily on murine blastocysts.32 Embryonic stem cells are derived from totipotent cells of the early mammalian embryo and are capable of unlimited, undifferentiated proliferation in vitro.33 Human embryonic stem cells can express high levels of telomerase activity, comparable with that expressed by cells isolated from germ lines and embryonic tissues.34 They can also form several cell types and simple tissue. Further understanding of cell tissue interactions and their relation with the extracellular matrix may eventually enable in vitro production of complex organs.35 In vitro manipulation of embryonic stem cells can be enhanced by nuclear transfer and cloning.36

Advances in stem cell technology have stimulated rapid growth in the understanding of embryonic and postnatal neural development. A population of neuronal stem cells capable of extended self renewal in addition to subsequent differentiation into both neurones and glia has already been identified.37 These common neurohaematopoietic stem cells can be isolated from the subventricular zone in the wall of the lateral ventricle of the brain. They divide in response to epidermal growth factor and fibroblast growth factor-2.38 Transplanted neuronal stem cells can integrate into an intact brain and differentiate into neuronal and glial cells. They may also function as haematopoietic stem cells when infused into irradiated mice.39 This last finding is controversial and may represent an artefact of the experimental technique, since only one contaminating haematopoietic stem cell would be needed to repopulate a mouse haematopoietic system. However, the reverse has also been shown, with stem cells derived from bone marrow entering through the brain-blood barrier, becoming fully differentiated, and displaying macrophage-like function (microglia).40

Initial clinical trials have shown that neurone replacement for neurovegetative diseases such as Parkinson's and Huntington's diseases is now feasible. Reports of transplantation of fetal striatal tissue in patients with mild to severe Huntington's disease suggest that transplantation of neuronal stem cells may improve some of the cognitive symptoms associated with the condition, as well as potentially modifying its clinical course.41 Neuronal stem cells can also be manipulated before grafting; they have been shown to respond to stimulation with fibroblast growth factor-2, and immortalised neural stem-like cells infected with viral vectors have been found to express factors that are related to neural repair.42

The existence of prostate stem cells is still a matter of debate.43 Nevertheless, the concept is interesting, mainly because of the possible analogy between effects of androgens on the prostate stem cells and that of cytokines on haematopoietic stem cells. Prostate stem cells could have important implications in the development of prostatic carcinoma.44

Understanding of liver regeneration has improved greatly since the initial description of oval cells as progeny of facultative stem cells.45 Hepatic stem cells, which are found in the interlobular bile ducts and possibly also in the canals of Hering, could have a large impact on the pathophysiology of hepatocellular carcinomas and cholangiocarcinomas.46,47

Limbal stem cells have been described at the junction between the cornea and sclerae.48 These cells are known to be progenitors of corneal epithelium. Keratolimbal allografts are a promising treatment for bilateral blindness,49 and limbal stem cells can now be safely obtained from living related donors.50

Stem cell technology is progressing as the result of multidisciplinary effort, with clinical applications of manipulated stem cells combining developments in transplantation and gene therapy. There are rather complex ethical issues related to the applications of cloning and nuclear transfer in human stem cells. Successful ex vivo manipulation of stem cells will depend on improved understanding of the interactions between cytokines and the extracellular matrix. Cytokines may decrease binding forces between stem cells and components of the stromal microenvironment, thus facilitating the migration of stem cells into the peripheral blood. Improvements in mobilisation schedules using growth factors, stem cell isolation, and purification procedures and techniques for both positive and negative purging (to reduce tumour cell contamination or to deplete T lymphocytes) are emerging. The possibility of ex vivo multiplication of stem cells to accelerate haematopoietic recovery or to provide sufficient stem cells from one extraction to support several cycles of high dose chemotherapy is under investigation. The applications for autologous stem cell transplantation should increase as it avoids the use of non-specific immunosuppressive therapy. Peripheral blood stem cells have advantages over bone marrow cells for autologous transplantation in that they show consistently faster haematopoietic reconstitution and can be collected on an outpatient basis.

Stem cells originating from solid tissue can potentially be applied in tissue repair. Techniques by which new genetic material is introduced into stem cells are being developed, and may lead to the cure of various inherited diseases by somatic gene therapy.

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Stem cell technology - PubMed Central (PMC)

Pluripotent stem cell of the inner cell mass of the blastocyst

Embryonic stem cells (ES cells or ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre-implantation embryo.[1][2] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. Isolating the embryoblast, or inner cell mass (ICM) results in destruction of the blastocyst, a process which raises ethical issues, including whether or not embryos at the pre-implantation stage have the same moral considerations as embryos in the post-implantation stage of development.[3][4]

Researchers are currently focusing heavily on the therapeutic potential of embryonic stem cells, with clinical use being the goal for many laboratories.[5] Potential uses include the treatment of diabetes and heart disease.[5] The cells are being studied to be used as clinical therapies, models of genetic disorders, and cellular/DNA repair. However, adverse effects in the research and clinical processes such as tumors and unwanted immune responses have also been reported.[6]

Embryonic stem cells (ESCs), derived from the blastocyst stage of early mammalian embryos, are distinguished by their ability to differentiate into any embryonic cell type and by their ability to self-renew. It is these traits that makes them valuable in the scientific and medical fields. ESCs have a normal karyotype, maintain high telomerase activity, and exhibit remarkable long-term proliferative potential.[7]

Embryonic stem cells of the inner cell mass are pluripotent, meaning they are able to differentiate to generate primitive ectoderm, which ultimately differentiates during gastrulation into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These germ layers generate each of the more than 220 cell types in the adult human body. When provided with the appropriate signals, ESCs initially form precursor cells that in subsequently differentiate into the desired cell types. Pluripotency distinguishes embryonic stem cells from adult stem cells, which are multipotent and can only produce a limited number of cell types.

Under defined conditions, embryonic stem cells are capable of self-renewing indefinitely in an undifferentiated state. Self-renewal conditions must prevent the cells from clumping and maintain an environment that supports an unspecialized state.[8] Typically this is done in the lab with media containing serum and leukemia inhibitory factor or serum-free media supplements with two inhibitory drugs ("2i"), the MEK inhibitor PD03259010 and GSK-3 inhibitor CHIR99021.[9]

ESCs divide very frequently due to a shortened G1 phase in their cell cycle. Rapid cell division allows the cells to quickly grow in number, but not size, which is important for early embryo development. In ESCs, cyclin A and cyclin E proteins involved in the G1/S transition are always expressed at high levels.[10] Cyclin-dependent kinases such as CDK2 that promote cell cycle progression are overactive, in part due to downregulation of their inhibitors.[11] Retinoblastoma proteins that inhibit the transcription factor E2F until the cell is ready to enter S phase are hyperphosphorylated and inactivated in ESCs, leading to continual expression of proliferation genes.[10] These changes result in accelerated cycles of cell division. Although high expression levels of pro-proliferative proteins and a shortened G1 phase have been linked to maintenance of pluripotency,[12][13] ESCs grown in serum-free 2i conditions do express hypo-phosphorylated active Retinoblastoma proteins and have an elongated G1 phase.[14] Despite this difference in the cell cycle when compared to ESCs grown in media containing serum these cells have similar pluripotent characteristics.[15] Pluripotency factors Oct4 and Nanog play a role in transcriptionally regulating the ESC cell cycle.[16][17]

Due to their plasticity and potentially unlimited capacity for self-renewal, embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. Pluripotent stem cells have shown promise in treating a number of varying conditions, including but not limited to: spinal cord injuries, age related macular degeneration, diabetes, neurodegenerative disorders (such as Parkinson's disease), AIDS, etc.[18] In addition to their potential in regenerative medicine, embryonic stem cells provide a possible alternative source of tissue/organs which serves as a possible solution to the donor shortage dilemma. There are some ethical controversies surrounding this though (see Ethical debate section below). Aside from these uses, ESCs can also be used for research on early human development, certain genetic disease, and in vitro toxicology testing.[7]

According to a 2002 article in PNAS, "Human embryonic stem cells have the potential to differentiate into various cell types, and, thus, may be useful as a source of cells for transplantation or tissue engineering."[19]

In tissue engineering, the use of stem cells have been recently discovered and are known to be of importance. In order to successfully engineer a tissue, the cells used must be able to perform specific biological function such as secretion of cytokines, signaling molecules, interacting with neighboring cells, and producing an extracellular matrix in the correct organization. Stem cells demonstrates these specific biological functions along with being able to self-renew and differentiate into one or more types of specialized cells. Embryonic stem cells is one of the current sources that are being considered for the use of tissue engineering.[20] The use of human embryonic stem cells have opened many new possibilities for tissue engineering, however, there are many hurdles that must be made before human embryonic stem cell can even be utilized. It is theorized that if embryonic stem cells can be altered to not evoke the immune response when implanted into the patient then this would be a revolutionary step in tissue engineering.[21]

However, embryonic stem cells are not limited to cell/tissue engineering.

Current research focuses on differentiating ESCs into a variety of cell types for eventual use as cell replacement therapies (CRTs). Some of the cell types that have or are currently being developed include cardiomyocytes (CM), neurons, hepatocytes, bone marrow cells, islet cells and endothelial cells.[22] However, the derivation of such cell types from ESCs is not without obstacles, therefore current research is focused on overcoming these barriers. For example, studies are underway to differentiate ESCs into tissue specific CMs and to eradicate their immature properties that distinguish them from adult CMs.[23]

Besides becoming an important alternative to organ transplants, ESCs are also being used in field of toxicology and as cellular screens to uncover new chemical entities (NCEs) that can be developed as small molecule drugs. Studies have shown that cardiomyocytes derived from ESCs are validated in vitro models to test drug responses and predict toxicity profiles.[22] ES derived cardiomyocytes have been shown to respond to pharmacological stimuli and hence can be used to assess cardiotoxicity like Torsades de Pointes.[30]

ESC-derived hepatocytes are also useful models that could be used in the preclinical stages of drug discovery. However, the development of hepatocytes from ESCs has proven to be challenging and this hinders the ability to test drug metabolism. Therefore, current research is focusing on establishing fully functional ESC-derived hepatocytes with stable phase I and II enzyme activity.[31]

Several new studies have started to address the concept of modeling genetic disorders with embryonic stem cells. Either by genetically manipulating the cells, or more recently, by deriving diseased cell lines identified by prenatal genetic diagnosis (PGD), modeling genetic disorders is something that has been accomplished with stem cells. This approach may very well prove valuable at studying disorders such as Fragile-X syndrome, Cystic fibrosis, and other genetic maladies that have no reliable model system.

Yury Verlinsky, a Russian-American medical researcher who specialized in embryo and cellular genetics (genetic cytology), developed prenatal diagnosis testing methods to determine genetic and chromosomal disorders a month and a half earlier than standard amniocentesis. The techniques are now used by many pregnant women and prospective parents, especially couples who have a history of genetic abnormalities or where the woman is over the age of 35 (when the risk of genetically related disorders is higher). In addition, by allowing parents to select an embryo without genetic disorders, they have the potential of saving the lives of siblings that already had similar disorders and diseases using cells from the disease free offspring.[32]

Differentiated somatic cells and ES cells use different strategies for dealing with DNA damage. For instance, human foreskin fibroblasts, one type of somatic cell, use non-homologous end joining (NHEJ), an error prone DNA repair process, as the primary pathway for repairing double-strand breaks (DSBs) during all cell cycle stages.[33] Because of its error-prone nature, NHEJ tends to produce mutations in a cell's clonal descendants.

ES cells use a different strategy to deal with DSBs.[34] Because ES cells give rise to all of the cell types of an organism including the cells of the germ line, mutations arising in ES cells due to faulty DNA repair are a more serious problem than in differentiated somatic cells. Consequently, robust mechanisms are needed in ES cells to repair DNA damages accurately, and if repair fails, to remove those cells with un-repaired DNA damages. Thus, mouse ES cells predominantly use high fidelity homologous recombinational repair (HRR) to repair DSBs.[34] This type of repair depends on the interaction of the two sister chromosomes[verification needed] formed during S phase and present together during the G2 phase of the cell cycle. HRR can accurately repair DSBs in one sister chromosome by using intact information from the other sister chromosome. Cells in the G1 phase of the cell cycle (i.e. after metaphase/cell division but prior the next round of replication) have only one copy of each chromosome (i.e. sister chromosomes aren't present). Mouse ES cells lack a G1 checkpoint and do not undergo cell cycle arrest upon acquiring DNA damage.[35] Rather they undergo programmed cell death (apoptosis) in response to DNA damage.[36] Apoptosis can be used as a fail-safe strategy to remove cells with un-repaired DNA damages in order to avoid mutation and progression to cancer.[37] Consistent with this strategy, mouse ES stem cells have a mutation frequency about 100-fold lower than that of isogenic mouse somatic cells.[38]

On January 23, 2009, Phase I clinical trials for transplantation of oligodendrocytes (a cell type of the brain and spinal cord) derived from human ES cells into spinal cord-injured individuals received approval from the U.S. Food and Drug Administration (FDA), marking it the world's first human ES cell human trial.[39] The study leading to this scientific advancement was conducted by Hans Keirstead and colleagues at the University of California, Irvine and supported by Geron Corporation of Menlo Park, CA, founded by Michael D. West, PhD. A previous experiment had shown an improvement in locomotor recovery in spinal cord-injured rats after a 7-day delayed transplantation of human ES cells that had been pushed into an oligodendrocytic lineage.[40] The phase I clinical study was designed to enroll about eight to ten paraplegics who have had their injuries no longer than two weeks before the trial begins, since the cells must be injected before scar tissue is able to form. The researchers emphasized that the injections were not expected to fully cure the patients and restore all mobility. Based on the results of the rodent trials, researchers speculated that restoration of myelin sheathes and an increase in mobility might occur. This first trial was primarily designed to test the safety of these procedures and if everything went well, it was hoped that it would lead to future studies that involve people with more severe disabilities.[41] The trial was put on hold in August 2009 due to FDA concerns regarding a small number of microscopic cysts found in several treated rat models but the hold was lifted on July 30, 2010.[42]

In October 2010 researchers enrolled and administered ESTs to the first patient at Shepherd Center in Atlanta.[43] The makers of the stem cell therapy, Geron Corporation, estimated that it would take several months for the stem cells to replicate and for the GRNOPC1 therapy to be evaluated for success or failure.

In November 2011 Geron announced it was halting the trial and dropping out of stem cell research for financial reasons, but would continue to monitor existing patients, and was attempting to find a partner that could continue their research.[44] In 2013 BioTime, led by CEO Dr. Michael D. West, acquired all of Geron's stem cell assets, with the stated intention of restarting Geron's embryonic stem cell-based clinical trial for spinal cord injury research.[45]

BioTime company Asterias Biotherapeutics (NYSE MKT: AST) was granted a $14.3 million Strategic Partnership Award by the California Institute for Regenerative Medicine (CIRM) to re-initiate the world's first embryonic stem cell-based human clinical trial, for spinal cord injury. Supported by California public funds, CIRM is the largest funder of stem cell-related research and development in the world.[46]

The award provides funding for Asterias to reinitiate clinical development of AST-OPC1 in subjects with spinal cord injury and to expand clinical testing of escalating doses in the target population intended for future pivotal trials.[46]

AST-OPC1 is a population of cells derived from human embryonic stem cells (hESCs) that contains oligodendrocyte progenitor cells (OPCs). OPCs and their mature derivatives called oligodendrocytes provide critical functional support for nerve cells in the spinal cord and brain. Asterias recently presented the results from phase 1 clinical trial testing of a low dose of AST-OPC1 in patients with neurologically complete thoracic spinal cord injury. The results showed that AST-OPC1 was successfully delivered to the injured spinal cord site. Patients followed 23 years after AST-OPC1 administration showed no evidence of serious adverse events associated with the cells in detailed follow-up assessments including frequent neurological exams and MRIs. Immune monitoring of subjects through one year post-transplantation showed no evidence of antibody-based or cellular immune responses to AST-OPC1. In four of the five subjects, serial MRI scans performed throughout the 23 year follow-up period indicate that reduced spinal cord cavitation may have occurred and that AST-OPC1 may have had some positive effects in reducing spinal cord tissue deterioration. There was no unexpected neurological degeneration or improvement in the five subjects in the trial as evaluated by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam.[46]

The Strategic Partnership III grant from CIRM will provide funding to Asterias to support the next clinical trial of AST-OPC1 in subjects with spinal cord injury, and for Asterias' product development efforts to refine and scale manufacturing methods to support later-stage trials and eventually commercialization. CIRM funding will be conditional on FDA approval for the trial, completion of a definitive agreement between Asterias and CIRM, and Asterias' continued progress toward the achievement of certain pre-defined project milestones.[46]

The major concern with the possible transplantation of ESC into patients as therapies is their ability to form tumors including teratoma.[47] Safety issues prompted the FDA to place a hold on the first ESC clinical trial, however no tumors were observed.

The main strategy to enhance the safety of ESC for potential clinical use is to differentiate the ESC into specific cell types (e.g. neurons, muscle, liver cells) that have reduced or eliminated ability to cause tumors. Following differentiation, the cells are subjected to sorting by flow cytometry for further purification. ESC are predicted to be inherently safer than IPS cells created with genetically integrating viral vectors because they are not genetically modified with genes such as c-Myc that are linked to cancer. Nonetheless, ESC express very high levels of the iPS inducing genes and these genes including Myc are essential for ESC self-renewal and pluripotency,[48] and potential strategies to improve safety by eliminating c-Myc expression are unlikely to preserve the cells' "stemness". However, N-myc and L-myc have been identified to induce iPS cells instead of c-myc with similar efficiency.[49]More recent protocols to induce pluripotency bypass these problems completely by using non-integrating RNA viral vectors such as sendai virus or mRNA transfection.

Due to the nature of embryonic stem cell research, there are a lot of controversial opinions on the topic. Since harvesting embryonic stem cells necessitates destroying the embryo from which those cells are obtained, the moral status of the embryo comes into question. Some people claim that the 5-day-old mass of cells is too young to achieve personhood or that the embryo, if donated from an IVF clinic (where labs typically acquire embryos), would otherwise go to medical waste anyway. Opponents of ESC research claim that an embryo is a human life, therefore destroying it is murder and the embryo must be protected under the same ethical view as a more developed human being.[50]

In vitro fertilization generates multiple embryos. The surplus of embryos is not clinically used or is unsuitable for implantation into the patient, and therefore may be donated by the donor with consent. Human embryonic stem cells can be derived from these donated embryos or additionally they can also be extracted from cloned embryos created using a cell from a patient and a donated egg through the process of somatic cell nuclear transfer.[63] The inner cell mass (cells of interest), from the blastocyst stage of the embryo, is separated from the trophectoderm, the cells that would differentiate into extra-embryonic tissue. Immunosurgery, the process in which antibodies are bound to the trophectoderm and removed by another solution, and mechanical dissection are performed to achieve separation. The resulting inner cell mass cells are plated onto cells that will supply support. The inner cell mass cells attach and expand further to form a human embryonic cell line, which are undifferentiated. These cells are fed daily and are enzymatically or mechanically separated every four to seven days. For differentiation to occur, the human embryonic stem cell line is removed from the supporting cells to form embryoid bodies, is co-cultured with a serum containing necessary signals, or is grafted in a three-dimensional scaffold to result.[64]

Embryonic stem cells are derived from the inner cell mass of the early embryo, which are harvested from the donor mother animal. Martin Evans and Matthew Kaufman reported a technique that delays embryo implantation, allowing the inner cell mass to increase. This process includes removing the donor mother's ovaries and dosing her with progesterone, changing the hormone environment, which causes the embryos to remain free in the uterus. After 46 days of this intrauterine culture, the embryos are harvested and grown in in vitro culture until the inner cell mass forms egg cylinder-like structures, which are dissociated into single cells, and plated on fibroblasts treated with mitomycin-c (to prevent fibroblast mitosis). Clonal cell lines are created by growing up a single cell. Evans and Kaufman showed that the cells grown out from these cultures could form teratomas and embryoid bodies, and differentiate in vitro, all of which indicating that the cells are pluripotent.[53]

Gail Martin derived and cultured her ES cells differently. She removed the embryos from the donor mother at approximately 76 hours after copulation and cultured them overnight in a medium containing serum. The following day, she removed the inner cell mass from the late blastocyst using microsurgery. The extracted inner cell mass was cultured on fibroblasts treated with mitomycin-c in a medium containing serum and conditioned by ES cells. After approximately one week, colonies of cells grew out. These cells grew in culture and demonstrated pluripotent characteristics, as demonstrated by the ability to form teratomas, differentiate in vitro, and form embryoid bodies. Martin referred to these cells as ES cells.[54]

It is now known that the feeder cells provide leukemia inhibitory factor (LIF) and serum provides bone morphogenetic proteins (BMPs) that are necessary to prevent ES cells from differentiating.[65][66] These factors are extremely important for the efficiency of deriving ES cells. Furthermore, it has been demonstrated that different mouse strains have different efficiencies for isolating ES cells.[67] Current uses for mouse ES cells include the generation of transgenic mice, including knockout mice. For human treatment, there is a need for patient specific pluripotent cells. Generation of human ES cells is more difficult and faces ethical issues. So, in addition to human ES cell research, many groups are focused on the generation of induced pluripotent stem cells (iPS cells).[68]

On August 23, 2006, the online edition of Nature scientific journal published a letter by Dr. Robert Lanza (medical director of Advanced Cell Technology in Worcester, MA) stating that his team had found a way to extract embryonic stem cells without destroying the actual embryo.[69] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding in the US, where federal funding was at the time limited to research using embryonic stem cell lines derived prior to August 2001. In March, 2009, the limitation was lifted.[70]

Human embryonic stem cells have also been derived by somatic cell nuclear transfer (SCNT).[71][72] This approach has also sometimes been referred to as "therapeutic cloning" because SCNT bears similarity to other kinds of cloning in that nuclei are transferred from a somatic cell into an enucleated zygote. However, in this case SCNT was used to produce embryonic stem cell lines in a lab, not living organisms via a pregnancy. The "therapeutic" part of the name is included because of the hope that SCNT produced embryonic stem cells could have clinical utility.

The iPSC technology was pioneered by Shinya Yamanaka's 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.[73] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."[74]

In 2007, it was shown that pluripotent stem cells, highly similar to embryonic stem cells, can be induced by the delivery of four factors (Oct3/4, Sox2, c-Myc, and Klf4) to differentiated cells.[75] Utilizing the four genes previously listed, the differentiated cells are "reprogrammed" into pluripotent stem cells, allowing for the generation of pluripotent/embryonic stem cells without the embryo. The morphology and growth factors of these lab induced pluripotent cells, are equivalent to embryonic stem cells, leading these cells to be known as "induced pluripotent stem cells" (iPS cells).[76] This observation was observed in mouse pluripotent stem cells, originally, but now can be performed in human adult fibroblasts using the same four genes. [77]

Because ethical concerns regarding embryonic stem cells typically are about their derivation from terminated embryos, it is believed that reprogramming to these "induced pluripotent stem cells" (iPS cells) may be less controversial.

This may enable the generation of patient specific ES cell lines that could potentially be used for cell replacement therapies. In addition, this will allow the generation of ES cell lines from patients with a variety of genetic diseases and will provide invaluable models to study those diseases.

However, as a first indication that the induced pluripotent stem cell (iPS) cell technology can in rapid succession lead to new cures, it was used by a research team headed by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to cure mice of sickle cell anemia, as reported by Science journal's online edition on December 6, 2007.[78][79]

On January 16, 2008, a California-based company, Stemagen, announced that they had created the first mature cloned human embryos from single skin cells taken from adults. These embryos can be harvested for patient matching embryonic stem cells.[80]

The online edition of Nature Medicine published a study on January 24, 2005, which stated that the human embryonic stem cells available for federally funded research are contaminated with non-human molecules from the culture medium used to grow the cells.[81] It is a common technique to use mouse cells and other animal cells to maintain the pluripotency of actively dividing stem cells. The problem was discovered when non-human sialic acid in the growth medium was found to compromise the potential uses of the embryonic stem cells in humans, according to scientists at the University of California, San Diego.[82]

However, a study published in the online edition of Lancet Medical Journal on March 8, 2005, detailed information about a new stem cell line that was derived from human embryos under completely cell- and serum-free conditions. After more than 6 months of undifferentiated proliferation, these cells demonstrated the potential to form derivatives of all three embryonic germ layers both in vitro and in teratomas. These properties were also successfully maintained (for more than 30 passages) with the established stem cell lines.[83]

Muse cells (Multi-lineage differentiating stress enduring cell) are non-cancerous pluripotent stem cell found in adults.[84][85] They were discovered in 2010 by Mari Dezawa and her research group.[84] Muse cells reside in the connective tissue of nearly every organ including the umbilical cord, bone marrow and peripheral blood.[86][84][87][88][89] They are collectable from commercially obtainable mesenchymal cells such as human fibroblasts, bone marrow-mesenchymal stem cells and adipose-derived stem cells.[90][91][92] Muse cells are able to generate cells representative of all three germ layers from a single cell both spontaneously and under cytokine induction. Expression of pluripotency genes and triploblastic differentiation are self-renewable over generations. Muse cells do not undergo teratoma formation when transplanted into a host environment in vivo, eradicating the risk of tumorigenesis through unbridled cell proliferation.[84]

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