ALG-055009, a THR-? agonist drug candidate in development as a treatment for NASH, demonstrated dose-dependent reductions in several atherogenic lipids and a favorable pharmacokinetic profile in subjects with hyperlipidemia

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Aligos Therapeutics Presents Clinical Data for its NASH Program and Nonclinical Data for its Chronic Hepatitis B Portfolio at AASLD’s The Liver...

IPS Cell Therapy Comments Off on Aligos Therapeutics Presents Clinical Data for its NASH Program and Nonclinical Data for its Chronic Hepatitis B Portfolio at AASLD’s The Liver… | November 6th, 2022

Data demonstrated treatment with TERN-501 resulted in time- and dose-dependent increases in sex hormone binding globulin (SHBG), a key marker linked to NASH histologic efficacy

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Terns Pharmaceuticals Highlights Results from Phase 1 Clinical Trial of TERN-501 at AASLD The Liver Meeting® 2022

IPS Cell Therapy Comments Off on Terns Pharmaceuticals Highlights Results from Phase 1 Clinical Trial of TERN-501 at AASLD The Liver Meeting® 2022 | November 6th, 2022

Media Advisory

Wednesday, August 31, 2022

At the National Institutes of Health, a surgical team successfully implanted a patch of tissue made from patient cells with the goal of treating advanced dry age-related macular degeneration (AMD), also known as geographic atrophy. Dry AMD is a leading cause of vision loss among older Americans and currently has no treatment.

The patient received the therapy as part of a clinical trial that is the first in the United States to use replacement tissues from patient-derived induced pluripotent stem (iPS) cells. The surgery was performed by Amir H. Kashani, M.D., Ph.D., associate professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine with assistance by Shilpa Kodati, M.D., staff clinician, NEI. The procedure was performed at the NIH Clinical Center in Bethesda, Maryland, under a phase 1/2a clinical trial to determine the therapys safety.

This iPS cell derived therapy was developed by the Ocular and Stem Cell Translational Research Section team led by Kapil Bharti, Ph.D., senior investigator at the National Eye Institute (NEI), part of NIH, in collaboration with FUJIFILM Cellular Dynamics Inc., and Opsis Therapeutics, based in Madison, Wisconsin. Safety and efficacy of this cell therapy was tested by the NEI preclinical team. Clinical-grade manufacturing of this cell therapy was performed at the Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, NIH.

This surgery is the culmination of 10 years of research and development at the NEI. In the NIH lab, the patients blood cells were converted to iPS cells, which can become almost any type of cell in the body. In this case, they were programmed to become retinal pigment epithelial (RPE) cells, the type of cell that degenerates in the advanced forms of dry AMD. RPE cells nourish and support light-sensing photoreceptors in the retina. In AMD, the loss of RPE leads to the loss of photoreceptors, which causes vision loss. This work was supported by the NIH Common Fund and NEI Intramural funding.

Kapil Bharti, Ph.D., senior investigator, Ocular and Stem Cell Translational Research Section, NEI

Brian Brooks, M.D., Ph.D., chief, Ophthalmic Genetics and Visual Function Branch, NEI

To schedule interviews with Drs. Bharti and Brooks, contact NEI at neinews@nei.nih.gov

NIH launches first U.S. clinical trial of patient-derived stem cell therapy to replace and repair dying cells in retina (News release)

NIH researchers rescue photoreceptors, prevent blindness in animal models of retinal degeneration (News release)

Autologous Transplantation of Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium for Geographic Atrophy Associated with Age-Related Macular Degeneration (Clinical trial information)

About the NEI: NEI leads the federal governments efforts to eliminate vision loss and improve quality of life through vision researchdriving innovation, fostering collaboration, expanding the vision workforce, and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to broaden opportunities for people with vision impairment. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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First U.S. patient receives autologous stem cell therapy to treat dry ...

IPS Cell Therapy Comments Off on First U.S. patient receives autologous stem cell therapy to treat dry … | October 29th, 2022

BORDEAUX, France, Oct. 11, 2022 /PRNewswire/ --TreeFrog Therapeutics,a biotechnology company developing stem cell-derived therapies in regenerative medicine and immuno-oncology based on the biomimetic C-Stemtechnology platform, and Invetech, a global leader in the development and production ofautomated manufacturing solutionsfor cell and advanced therapies, today announced the delivery of a GMP-grade cell encapsulation device using the C-Stemtechnology. The machine will be transferred in 2023 to a contract development and manufacturing organization (CDMO) to produce TreeFrog's cell therapy candidate for Parkinson's disease, with the aim of a first-in-human trial in 2024.Over 2023, Invetech will deliver three additional GMP encapsulation devices to support TreeFrog's in-house and partnered cell therapy programs in regenerative medicine and immuno-oncology.

TreeFrogs C-Stem technology generates alginate capsules seeded with induced pluripotent stem cells (iPSCs) at very high speed. Engineered to mimic the in vivo stem cell niche, the capsules allow iPSCs to grow exponentially in 3D, and to differentiate into ready-to-transplant functional microtissues.

Blending microfluidics and stem cell biology, TreeFrog's C-Stemtechnology generates alginate capsules seeded with induced pluripotent stem cells (iPSCs) at very high speed. Engineered to mimic the in vivo stem cell niche, the capsules allow iPSCs to grow exponentially in 3D, and to differentiate into ready-to-transplant functional microtissues. And because alginate is both porous and highly resistant, encapsulated iPSCs can be expanded and differentiated in large-scale bioreactors without suffering from impeller-induced shear stress.

"TreeFrog Therapeutics introduces a breakthrough technology for cell therapy, which impacts scale, quality, as well as the efficacy and safety potential of cellular products. Automating this disruptive technology and turning it into a robust GMP-grade instrument is a tremendous achievement for our team. This deliverable is the result of a very fruitful and demanding collaboration with TreeFrog's engineers in biophysics and bioproduction over the past four years. We're now eager to learn how the neural microtissues produced with C-Stemwill perform in the clinic." Anthony Annibale, Global VP Commercial at Invetech.

Started in 2019, the collaboration between TreeFrog and Invetech led to the delivery of a prototype in October 2020. With this research-grade machine, TreeFrog demonstrated the scalability of C-Stem, moving within six months from milliliter-scale to 10-liter bioreactors. In June 2021, the company announced the production of two single-batches of 15 billion iPSCs in 10L bioreactors with an unprecedented 275-fold amplification per week, striking reproducibility and best-in-class cell quality. The new GMP-grade device delivered by Invetech features the same technical specifications. The machine generates over 1,000 capsules per second, allowing to seed bioreactors from 200mL to 10L. However, the device was entirely redesigned to fit bioproduction standards.

"With the GMP device, our main challenge was to minimize the learning curve for operators, so as to facilitate tech transfer. Invetech and our team did an outstanding job in terms of automation and industrial design to make the device both robust and easy to use. As an inventor, I am so proud of the journey of the C-Stemtechnology. Many elements have been changed and improved on the way, and now comes the time to put the platform in the hands of real-world users to make real products." Kevin Alessandri, Ph.D., co-founder and chief technology officer, TreeFrog Therapeutics

"In October 2020, we announced that we were planning for the delivery of a GMP encapsulation device by the end of 2022. Exactly two years after, we're right on time. I guess this machine testifies to the outstanding execution capacity of TreeFrog and Invetech. But more importantly, this machine constitutes a key milestone. Our platform can now be used to manufacture clinical-grade cell therapy products. Our plan is to accelerate the translation of our in-house and partnered programs to the clinic, with a focus on immuno-oncology and regenerative medicine applications." Frederic Desdouits, Ph.D., chief executive officer, TreeFrog Therapeutics

About Invetech

Invetech helps cell and gene therapy developers to visualize, strategize and manage the future. With proven processes, expert insights and full-spectrum services, we swiftly accelerate life-changing therapies from the clinic to commercial-scale manufacturing. Through our ready-to-run, preconfigured systems, our custom and configurable technology platforms and automated production systems, we assure predictable, reproducible products of the highest quality and efficacy. Our integrated approach brings together biological scientists, engineers, designers and program managers to deliver successful, cost-effective market offerings to more people, more quickly. Working in close collaboration with early-stage and mature life sciences companies, we are committed to advancing the next generation of vital, emerging therapies to revolutionize healthcare and precision medicine.invetechgroup.com

About TreeFrog Therapeutics

TreeFrog Therapeutics is a French-based biotech company aiming to unlock access to cell therapies for millions of patients. Bringing together over 100 biophysicists, cell biologists and bioproduction engineers, TreeFrog Therapeutics raised $82M over the past 3 years to advance a pipeline of stem cell-based therapies in immuno-oncology and regenerative medicine. In 2022, the company opened technological hubs in Boston, USA, and Kobe, Japan, with the aim of driving the adoption of the C-Stemplatform and establish strategic alliances with leading academic, biotech and industry players in the field of cell therapy.www.treefrog.fr

Media ContactsPierre-Emmanuel GaultierTreeFrog Therapeutics+ 33 6 45 77 42 58pierre@treefrog.fr

Marisa ReinosoInvetech+1 858 437 1061marisa.reinoso@invetechgroup.com

TreeFrog Therapeutics is a French-based biotech company aiming to unlock access to cell therapies for millions of patients. Bringing together over 100 biophysicists, cell biologists and bioproduction engineers, TreeFrog Therapeutics raised $82M over the past 3 years to advance a pipeline of stem cell-based therapies in immuno-oncology and regenerative medicine.

Invetech logo (PRNewsFoto/Invetech)

Cision

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SOURCE Invetech; Treefrog Therapeutics

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BREAKTHROUGH TECHNOLOGY FOR IPS-DERIVED CELL THERAPIES TURNED INTO GMP PLATFORM BY TREEFROG THERAPEUTICS & INVETECH - Yahoo Finance

IPS Cell Therapy Comments Off on BREAKTHROUGH TECHNOLOGY FOR IPS-DERIVED CELL THERAPIES TURNED INTO GMP PLATFORM BY TREEFROG THERAPEUTICS & INVETECH – Yahoo Finance | October 13th, 2022

AMSBIO has published an interview with Professor Marius Wernig from Stanford University, Pathology Stem Cell Institute that discusses what could be the worlds first widely applicable curative treatment for Epidermolysis Bullosa (EB).

This rare genetic disease causes chronic and incredibly painful skin wounds that often lead to an aggressive form of skin cancer and eventual death.

While various cell-therapy approaches have been attempted, Professor Wernig and collaborators identified the need for induced pluripotent stem cells (iPSCs), and how they could become used to treat EB in a more efficient, applicable, and commercially viable manner.

In the past, the only way Professor Wernigs research group could grow iPSCs cells with a normal karyotype over longer periods of time was on mouse feeder cells with serum. This combination of mouse cell co-culture and undefined bovine serum set was not a suitable methodology as it was almost impossible to perform in compliance with FDA safety standards.

Professor Wernig describes how StemFit Basic03 clinical grade stem cell culture medium, available from AMSBIO has allowed his research group to safely expand their cells using an FDA compliant protocol. While there are still hurdles to climb before a cure for EB is fully realised, using StemFit Basic03 has solved the challenge of reproducibly growing clinical grade iPSCs.

Read the full interview.

Completely free of animal- and human-derived components StemFit Basic03 provides highly stable and reproducible culture condition for Induced Pluripotent Stem and Embryonic Stem cells under feeder-free conditions during the reprogramming, expansion, and differentiation phases of stem cell culture. StemFit Basic03 combines high colony forming efficiency with lower than standard media volume consumption to offer cost effective colony expansion when compared to leading competitors.

More information online

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iPS-Cell Based Cell Therapies for Genetic Skin Disease

IPS Cell Therapy Comments Off on iPS-Cell Based Cell Therapies for Genetic Skin Disease | October 5th, 2022

JCR Pharmaceuticals Co., Ltd. and Sysmex Corporation announced that they have established a joint venture(hereafter the "joint venture") for carrying out research and development, manufacture and sales of cell-based regenerative medicine products including hematopoietic stem cells and other stem cells. In recent years, the significant potential of regenerative medicine and cell therapy have been established in particular in areas that have traditionally been difficult to address with conventional chemically synthesized low molecular weight drugs1 or biopharmaceuticals2, such as the restoration of tissues and functions lost as a result of aging, illness, autoimmune diseases, or cancer. In particular, research and development on the therapeutic application of stem cells including hematopoietic stem cells, mesenchymal stem cells, and iPS cells have generated significant attention. Since its inception, JCR has been engaged in the research, development, manufacturing and sales of pharmaceutical products using regenerative medicine, genetic engineering, and gene therapy technologies to advance therapies in the rare disease field. This is exemplified in the field of regenerative medicine, by the approval of TEMCELL HS Inj.3, the first allogeneic regenerativemedicine in Japan (Non-proprietary name: Human (allogeneic) bone marrow-derived mesenchymal stem cells) in February 2016 for the treatment of acute graft-versus-host disease (acute GVHD)4, a serious complication that develops after hematopoietic stem cell transplantation. In recent years, JCR has further streamlined and integrated its expertise around the establishment of groundbreaking medicines for the advancement of highly innovative medicines that could not be developed without such groundbreaking technologies. In the joint venture, the two companies aim to realize the social implementation of regenerative medicine and cell therapy by integrating JCR's expertise in developing, manufacturing and marketing regenerative medicine products, with Sysmex's expertise in quality control testing technology and knowledge of workflows efficiency using robotics technology, including IoT. AlliedCel Corporation, which is the corporate name of the joint venture following prior discussions regarding the alliance both companies, was established on October 3, 2022. The joint venture will advance programs of the potential for technology development and commercialization, including the project currently being promoted by both companies using hematopoietic stem cell proliferation technology. The name AlliedCel stands for the joint venture's aspiration to integrate knowledge and expertise from a broad set of collaborators and stakeholders including business partners, patients and their families, with the united goal of unleashing the power of cells in supporting patients in their needfor life-changing therapies. Through the research and development of regenerative medicineproducts using diverse cells such as stem cells, AlliedCel aims to provide appropriate treatmentoptions to patients and improve their prognosis.

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Jcr Pharmaceuticals Co., Ltd. and Sysmex Establish A Joint Venture in the Field of Regenerative Medicine and Cell Therapy - Marketscreener.com

IPS Cell Therapy Comments Off on Jcr Pharmaceuticals Co., Ltd. and Sysmex Establish A Joint Venture in the Field of Regenerative Medicine and Cell Therapy – Marketscreener.com | October 5th, 2022

MeiraGTx

Multiple Poster Presentations Highlight Versatility and Novelty of MeiraGTxs Technology Platforms for Gene and Cell Therapy

LONDONandNEW YORK, Oct. 04, 2022 (GLOBE NEWSWIRE) -- MeiraGTx Holdings plc(Nasdaq: MGTX), a vertically integrated, clinical stage gene therapy company, today announced the Company will exhibit 15 poster presentations at the European Society of Gene and Cell Therapy (ESGCT) 2022 Annual Congress, which will be held from October 11-14, 2022, in Edinburgh, Scotland.

The posters will include data from MeiraGTxs novel gene regulation platform, including the first data demonstrating the potential to regulate CAR-T, as well as data from the Companys promoter platforms and several new, optimized pre-clinical programs addressing severe unmet needs for indications such as amyotrophic lateral sclerosis (ALS) and Wilsons disease. In addition, the Company will have presentations on its proprietary viral vector manufacturing technology and potency assay development.

Were pleased to present data illustrating the depth and versatility of MeiraGTxs scientific platforms, said Alexandria Forbes, Ph.D., president and chief executive officer of MeiraGTx. The 15 published abstracts at this years ESGCT Congress reflect the extraordinary productivity of our research efforts in developing new technologies and applying them to the design of optimized genetic medicines, as well as innovation in manufacturing and process development technology. I am particularly excited for us to present our riboswitch gene regulation technology applied to cell therapy for the first time, in this case the regulation of CAR-Ts, which is a huge area of scientific and clinical interest, continued Dr. Forbes. We look forward to presenting these data highlighting our innovative platform technologies and broad R&D capabilities.

Abstract Title (P101): AI-driven promoter optimization at MeiraGTxSession Title: Advances in viral and non-viral vector designDate: October 12, 2022

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Abstract Title (P124): Promoter Engineering Platform at MeiraGTxSession Title: Advances in viral and non-viral vector designDate: October 13, 2022

Abstract Title (P243): UPF1 delivered by novel expression-enhanced promoters protects cultured neurons in a genetic ALS modelSession Title: CNS and sensoryDate: October 12, 2022

Abstract Title (P254): Optimization and scale-up of AAV2-AQP1 production using a novel transient transfection agentSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P264): Designing and screening formulations to improve manufacturability and distribution of AAV gene therapiesSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P270): Use of anion exchange chromatography to provide high empty AAV capsid removal and product yieldsSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P320): Multivariate analysis for increased understanding of MeiraGTx upstream processSession Title: Developments in manufacturing and scale upDate: October 13, 2022

Abstract Title (P362): Development of AAV-UPF1 gene therapy to rescue ALS pathophysiology using microfluidic platformsSession Title: Disease models (iPS derived and organoids)Date: October 13, 2022

Abstract Title (P399): Titratable and reversible control of CAR-T cell receptor and activity by riboswitch via oral small moleculeSession Title: Engineered T and NK CARs and beyondDate: October 12, 2022

Abstract Title (P436): Novel riboswitches regulate AAV-delivered transgene expression in mammals via oral small molecule inducersSession Title: Gene and epigenetic editingDate: October 13, 2022

Abstract Title (P553): Development of optimized ATP7B gene therapy vectors for the treatment of Wilsons Disease with increased potencySession Title: Metabolic diseasesDate: October 12, 2022

Abstract Title (P554): A CNS-targeted gene therapy for the treatment of obesitySession Title: Metabolic diseasesDate: October 13, 2022

Abstract Title (561): Riboswitch-controlled delivery of therapeutic hormones for gene therapySession Title: Metabolic diseasesDate: October 12, 2022

Abstract Title (P622): Riboswitch-controlled delivery of therapeutic antibodies for gene therapySession Title: OtherDate: October 13, 2022

Abstract Title (P630): Improving AAV in vitro transducibility for cell-based potency assay developmentSession Title: OtherDate: October 13, 2022

About MeiraGTxMeiraGTx (Nasdaq: MGTX) is a vertically integrated, clinical stage gene therapy company with six programs in clinical development and a broad pipeline of preclinical and research programs. MeiraGTx has core capabilities in viral vector design and optimization and gene therapy manufacturing, and a transformative gene regulation platform technology which allows tight, dose responsive control of gene expression by oral small molecules with dynamic range that can exceed 5000-fold. Led by an experienced management team, MeiraGTx has taken a portfolio approach by licensing, acquiring, and developing technologies that give depth across both product candidates and indications. MeiraGTxs initial focus is on three distinct areas of unmet medical need: ocular, including inherited retinal diseases and large degenerative ocular diseases, neurodegenerative diseases, and severe forms of xerostomia. Though initially focusing on the eye, central nervous system, and salivary gland, MeiraGTx plans to expand its focus to develop additional gene therapy treatments for patients suffering from a range of serious diseases.

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

Forward Looking StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding our product candidate development and our pre-clinical data and reporting of such data and the timing of results of data, including in light of the COVID-19 pandemic, as well as statements that include the words expect, will, intend, plan, believe, project, forecast, estimate, may, could, should, would, continue, anticipate and similar statements of a future or forward-looking nature. These forward-looking statements are based on managements current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, our incurrence of significant losses; any inability to achieve or maintain profitability, raise additional capital, repay our debt obligations, identify additional and develop existing product candidates, successfully execute strategic priorities, bring product candidates to market, expansion of our manufacturing facilities and processes, successfully enroll patients in and complete clinical trials, accurately predict growth assumptions, recognize benefits of any orphan drug designations, retain key personnel or attract qualified employees, or incur expected levels of operating expenses; the impact of the COVID-19 pandemic on the status, enrollment, timing and results of our clinical trials and on our business, results of operations and financial condition; failure of early data to predict eventual outcomes; failure to obtain FDA or other regulatory approval for product candidates within expected time frames or at all; the novel nature and impact of negative public opinion of gene therapy; failure to comply with ongoing regulatory obligations; contamination or shortage of raw materials or other manufacturing issues; changes in healthcare laws; risks associated with our international operations; significant competition in the pharmaceutical and biotechnology industries; dependence on third parties; risks related to intellectual property; changes in tax policy or treatment; our ability to utilize our loss and tax credit carryforwards; litigation risks; and the other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, as such factors may be updated from time to time in our other filings with the SEC, which are accessible on the SECs website at http://www.sec.gov. These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent managements estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, unless required by law, we disclaim any obligation to do so, even if subsequent events cause our views to change. Thus, one should not assume that our silence over time means that actual events are bearing out as expressed or implied in such forward-looking statements. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release.

Contacts

Investors:MeiraGTxInvestors@meiragtx.com

Media:Jason Braco, Ph.D.LifeSci Communicationsjbraco@lifescicomms.com

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MeiraGTx Announces the Upcoming Presentation of 15 Abstracts at the European Society of Gene and Cell Therapy (ESGCT) 2022 Annual Congress - Yahoo...

IPS Cell Therapy Comments Off on MeiraGTx Announces the Upcoming Presentation of 15 Abstracts at the European Society of Gene and Cell Therapy (ESGCT) 2022 Annual Congress – Yahoo… | October 5th, 2022

The global stem cell market size is expected to reach USD 19.13 Billion in 2028 at a CAGR of 8.4% during the forecast period, according to the latest report by Reports and Data.

The globalstem cell marketsize is expected to reach USD 19.13 Billion in 2028 at a CAGR of 8.4% during the forecast period, according to the latest report by Reports and Data. Growing adoption of stem cell therapies to treat chronic and rare diseases, rising number of clinical trials for regenerative medicine globally, and rapid progress in stem cell research are key factors expected to drive market revenue growth over the forecast period. In addition, increasing investment by major pharmaceutical and biotechnology companies, advancements in regenerative medicine, and development of advanced gene editing and tissue engineering techniques are also expected to contribute to revenue growth of the market going ahead.

Stem cells are unspecialized cells that have the ability to develop into different types of cells such as liver cells, muscle cells, and brain cells, among others. Stem cells have remarkable ability of self-renewal in undifferentiated state and can differentiate into various cell types with specific functions under appropriate triggers. Stem cells have played a major role in regenerative medicine, with increasing focus on stem cells of human origin such as adult stem cells, somatic stem cells, and embryonic stem cells. These cells can be used to regenerate human cells, organs, and tissues and have the capability to restore normal function after disease or debilitating injury. During embryonic development, stem cells can form cells of all three germ layers mesoderm, endoderm, and ectoderm. They play a crucial role in repair system of body and normal turnover of regenerative organs such as skin and blood, and this has boosted their importance in medical therapies for the treatment of various degenerative illnesses.

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

Increasing investment to accelerate stem cell research, rapid adoption of stem cell therapies for the treatment of chronic and neurodegenerative disorders, and the increasing number of clinical trials across the globe are some key factors expected to drive market growth Our Expert Review

Recent advancements in stem cell biology and research have enhanced the application scope of stem cell therapy in treating diseases wherein currently available medical therapies have failed to cure, prevent progression, or alleviate symptoms. This is also a key factor expected to contribute to revenue growth of the market over the forecast period. However, ethical issues and political controversies, concerns related to immunity, and stringent regulatory policies associated with stem cell research are some key factors expected to restrain market growth to a certain extent over the forecast period.

Some Key Highlights from the Report:

Asia Pacific is expected to lead the market growth over the coming years owing to rapid advancements in the healthcare sector in APAC countries such as India, China, and Japan. North America is anticipated to register the highest market growth over the forecast period attributed to the increasing availability of robust healthcare and clinical settings, legalization of medical marijuana, favorable reimbursement scenario, presence of key market players, and rapid technological advancements in the region.

The growing popularity of over-the-counter medications driving market growth

Growing incidence of acute and chronic diseases and lesser access to advanced medical facilities owing to low disposable income levels are driving the demand for over-the-counter medications. Availability of generic and low-cost alternatives to medical therapies are some other factors playing a major role in driving demand for over-the-counter medications.

Restriction on product launches and R&D activities to hamper the market growth

The imposition of strict government regulations and shortage of funds has put a halt on product launches and R&D activities and is expected to restrain market growth over the forecast period. In addition, the launch of expensive drugs and therapies and increasing regulations regarding safety and approvals are also hampering the market growth.

Competitive Landscape:

The global market comprises various market players operating at regional and global levels. These key players are adopting various strategies such as R&D investments, license agreements, partnerships, mergers and acquisitions, collaborations, and joint ventures to gain a robust footing in the market.

Top Companies Profiled in the Report:

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

Stem Cells Market Segmentation:

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)

Regional Outlook:

Frequently asked questions addressed in the report:

Thank you for reading our report. For more details please connect with us and our team will ensure the report is customized to meet all the needs of clients. The report also offers a comprehensive regional analysis and specific countries can be included in the report according to the requirements.

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Stem Cells Market Size Expected to Reach USD 19.31 Billion by 2028: Increasing Number of Clinical Trials Across the Globe - Digital Journal

IPS Cell Therapy Comments Off on Stem Cells Market Size Expected to Reach USD 19.31 Billion by 2028: Increasing Number of Clinical Trials Across the Globe – Digital Journal | September 27th, 2022

Specially treated stem cells derived from a single individual have been successfully implanted into that same individuals eyes in a first-of-its-kind clinical trial testing ways to treat advanced dry age-related macular degeneration (AMD).

The therapy, currently in its first phase of testing to ensure that its safe for humans, involves harvesting and processing a persons blood cells and using them to replace the persons retinal cells that had succumbed to AMD, a leading cause of vision loss globally.

The procedure was performed by researchers from the National Eye Institute (NEI), a branch of the National Institutes of Health in Bethesda, Maryland, and from the Wilmer Eye Institute at Johns Hopkins School of Medicine in Baltimore. The NIH researchers have been working on the new treatment for a decade.

The scientists, who previously demonstrated the safety and effectiveness of the therapy in rats and pigs, took blood cells from the patient and, in the laboratory, converted them into patient-derived induced pluripotent stem (iPS) cells. These immature, undifferentiated cells have no assigned function in the body, which means they can assume many forms. The researchers programmed these particular iPS cells to become retinal pigment epithelial (RPE) cells, the type that die in AMD and lead to late-stage dry AMD.

In healthy eyes, RPE cells supply oxygen to photoreceptors, the light-sensing cells in the retina at the back of the eyeball. The death of RPE cells virtually dooms the photoreceptors, resulting in vision loss. The idea behind the new therapy is to replace dying RPE cells with patient-derived induced iPS ones, strengthening the health of the remaining photoreceptors.

Before being transplanted, the iPS-derived cells were grown in sheets one cell thick on a biodegradable scaffold designed to promote their integration into the retina. The researchers positioned the resulting patch between atrophied host RPE cells and the photoreceptors using a specially created surgical tool.

The patient received the transplanted cells during the summer and will be followed for a year as researchers monitor overall eye health, including retina stability, and whether any inflammation or bleeding develop, says Kapil Bharti, PhD, a senior investigator at the NEI and for the clinical trial.

Safety data are critical for any new drug, says Gareth Lema, MD, PhD, a vitreoretinal surgeon at New York Eye & Ear Infirmary, a division of the Mount Sinai Health System. Stem cells have added complexity in that they are living tissue, Dr. Lema says. Precise differentiation is necessary for them to fulfill their intended therapeutic effect and not cause harm."

This therapy also requires a surgical procedure to implant the cells, Lema says, adding that its an exquisitely elegant surgery, but introduces further risk of harm. For those reasons, he says, Patients must know that ocular stem cell therapies should only be attempted within the regulated environment of a nationally registered clinical trial.

The rules of a clinical trial dont generally allow specifics to be discussed this early in the process, says Dr. Bharti. Announcing that we were able to successfully transplant the cells now hopefully allows us to recruit more patients, since we can take up to 12 in this phase, he says. We also hope that it will give some optimism to patients with dry AMD and to researchers studying it.

It took seven months to develop the implanted cells, says Bharti, and although the federal Food and Drug Administration (FDA) approved the clinical trial in 2019, the onset of the COVID-19 pandemic delayed the start by two years, he says.

Macular degeneration comprises several stages of disease within the macula, the critical portion of the retina responsible for straight-ahead vision. Aging causes retinal cells to deteriorate, generating debris, or drusen, within the macula, setting the stage for early (aka dry) AMD. Geographic atrophy represents a more advanced stage. If the disease progresses to the relatively rare wet AMD, so named for the leaking of blood into the macula, central vision can be snuffed out.

Risk of AMD increases with age, particularly among people who are white, have a history of smoking, or have a family history of the disease.

Treatment to slow wet AMDs progression includes eye injections with anti-VEGF (or VEGF-A for vascular endothelial growth factor antagonists), a medication that halts the growth of unstable, leaky blood vessels in the eye. Some people may undergo photodynamic therapy, which combines injections and laser treatments.

Currently, there is no cure for dry AMD; it cant be reversed. Nor are there treatments to reliably stop its onset or progression for everyone at every stage of the disease. (Research has confirmed that a specialized blend of vitamins and minerals, available over the counter as AREDS, or Age-Related Eye Disease Studies supplements, reduces the risk of AMDs progression from intermediate to advanced stages.)

There are other, ongoing clinical trials for the treatment of dry AMD. Regenerative Patch Technologies, in Menlo Park, California, for example, is a little further along in testing a different stem cell treatment. Patients have been followed for three years, and 27 percent have shown vision improvement, says Jane Lebkowski, PhD, the companys president. There are a number of AMD clinical trials ongoing in the U.S., and patients should ask their ophthalmologists about trials that might be appropriate.

ClinicalTrials.gov, the NIHs clinical trials database, lists close to 300 AMD clinical trials at various stages in the United States.

Ferhina Ali, MD, MPH, a retinal specialist at the Westchester Medical Center in Valhalla, New York, who isnt involved in the trial, describes the newest stem cell therapy as elegant and pioneering. These are early stages but there is tremendous potential as a first-in-kind surgically implanted stem cell therapy and as a way to achieve vision gains in dry macular degeneration, Dr. Ali says.

Bharti says that in laboratory animals the implanted cells behaved as retinal cells should maintaining the retinas integrity. Over the next few years, he and his colleagues will determine whether they function effectively in humans.

Does that mean, however, that the same AMD disease process that destroyed the original retinal cells could destroy the transplanted ones? It takes 40 to 60 years to damage human cells, Bharti says, and if we get that long with the transplanted cells, well take it.

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Implanting a Patient's Own Reprogrammed Stem Cells Shows Early Positive Results for Treating Dry AMD - Everyday Health

IPS Cell Therapy Comments Off on Implanting a Patient’s Own Reprogrammed Stem Cells Shows Early Positive Results for Treating Dry AMD – Everyday Health | September 19th, 2022

In the present study, we derived two particularly noteworthy results. First, nearly half of the institutions that responded to the study were either currently providing UCB to private banks during the study period or had done so in the past. Second, some institutions were found to provide UCB not only to private banks but also to companies, research institutions, and medical treatment facilities.

During the present study, the APHSCT, along with related ministerial ordinances and guidelines, stipulated how public banks preserve and manage UCB. However, during the study period, these laws and regulations did not require the institutions that handled childbirth to keep records, except when providing UCB to public banks. Consequently, no one knew how many institutions handling childbirth supplied UCB to private banks or the status of UCB distribution. The present study determined that 34.4% of institutions handling childbirth currently provide UCB to private banks, while 16.1% of institutions did so in the past. Our study reported for the first time that these percentages far outstrip those for UCB supply to public banks (6.1% and 8.0%, respectively). These low percentages may be related to the low number of institutions handling childbirth in Japan partnered with public banks (96 institutions as of January 18, 2021) [14,15,16,17,18,19].

However, from the standpoint of appropriate collection, safe preservation, and effective usage of UCB, public and private banks should be regulated according to more uniform standards. More than one-fourth of institutions that provide or have provided UCB to private banks did not provide explanations about UCB collection to UCB donors, while nearly 20% of institutions did not obtain consent. Donors of UCB choose to have their UCB preserved and are also users of UCB who entrust their UCB to private banks, a state of affairs that may lead to the opinion that it is not that important for institutions handling childbirth to provide explanations or obtain consent. However, an MHLW survey reported that private banks do not provide sufficient explanations to users in advance [20]. This state of affairs may be related to the absence of regulations in private banks in Japan.

Even before we demonstrated problems with private banks in Japan in the present study with empirical data, these problems were already known anecdotally, which led many academic associations to issue warnings. In 2002, the Japan Society for Hematopoietic Cell Transplantation issued a statement declaring that private banks were almost completely ineffective, except in cases such as patients with refractory blood diseases within ones own family and that regulations were necessary to ensure proper technical guidelines and safety [21]. In addition, the Japan Association of Obstetricians and Gynecologists declared in 2002 that sufficient understanding was necessary regarding the status and background of private storage of UCB and that careful steps were required to ensure that private banks do not simply use UCB for profit [22].

However, as we analyzed the results of the present study, a relevant concern came to pass. In 2017, physicians who administered UCB to patients without notifying government authorities were found guilty of violating the Act on the Safety of Regenerative Medicine, with the vendor who sold the UCB charged as an accomplice [23, 24]. The UCB sold by the vendor leaked from a private bank that had gone bankrupt in 2009. However, the charge in this case was providing regenerative medicine to patients without reporting it to the MHLW; there was no law targeting the sale of the leaked UCB itself, which was, therefore, beyond the scope of legal penalty [25].

Spurred by the case described above, the MHLW conducted a survey of private UCB banks in Japan [20]. Of the seven vendors whose activities could be confirmed at the time of the survey, six responded; one of these vendors only distributed UCB without preserving it. The UCB held by the remaining five vendors constituted a supply for a total of 45,800 people; roughly 2,100 peoples worth of UCB had not been disposed after the vendors contracts with the donors had ended. One vendor provided UCB to a third party (roughly 160 times). The three vendors involved in the above case later went out of business [26].

Taking the case seriously, the MHLW revised the APHSCT to generally prohibit the collection, preparation, storage, testing, and delivery of UCB for transplantation as a business by entities other than public banks. The revision also stipulated that UCB for transplantation may not be delivered by anyone for commercial purposes. However, these prohibitions do not apply when a public bank delivers UCB, when UCB is used in the treatment of a blood relative to the donor, or when approval is granted by the MHLW. Violations of these prohibitions are subject to criminal penalties. Consequently, the two private banks that obtained approval from the MHLW were permitted to continue their activities.

However, regardless of legal permission, there is still the question of whether private UCB banks, which handle UCB for profit, are ethically permissible. For example, the 2004 European Commissions Group on Ethics in Science and New Technologies stated that while they did not completely disavow for-profit biobank activities, these activities engender ethical criticism. The group also stated that the human body in principle is not an object of commercial value and recommended that private biobank activities operate under strict conditions such as appropriate management by regulatory authorities [27]. Meanwhile, a non-Japanese study has reported that the possibility of UCB being used 20years later by the person who requested its preservation or by their family is an incredibly low 0.040.0005% [28]. The extent to which this information is explained to potential private bank users is unknown. In fact, the previously cited survey by the MHLW indicated that the role of public UCB banks and the actual utility of the UCB stored in the private banks were not sufficiently explained to users [20]. Future research must thoroughly examine the status of UCB private banks following revision of the law and compare the results of this examination to the findings of the present study.

A small number of institutions handling childbirth surveyed in the present study responded that they currently provide or used to provide UCB to medical treatment facilities (2.6%), research institutions (5.9%), companies (2.2%), or foreign medical treatment facilities, research institutions, or companies (0.3%). Some institutions handling childbirth also either currently store or used to store UCB themselves for treatment or research (2.3% and 3.2%, respectively). This aspect of the status of UCB distribution has never been demonstrated in a previous study.

Since the revision of the APHSCT, the delivery of UCB for transplantation has been strictly prohibited except in the cases of provision to a public bank, provision to a private bank approved by the MHLW, and use for treatment by a blood relative. Thus, it is currently considered illegal for institutions handling childbirth to deliver UCB to other facilities domestically or internationally or to store UCB themselves for treatment purposes. However, the revised law still does not apply to the handling of UCB for research purposes, that is, basic studies and the development of treatments. In addition, while there are laws and local ordinances that call for the incineration or burial of UCB according to specific methods, these regulations generallydo not cover the delivery of UCB for research purposes.

At a glance, there would seem to be no problem with an institution that handles childbirth providing UCB to a third party or storing UCB itself for research purposes. However, the results of the present study, which found that a certain number of institutions handling childbirth do not provide explanations or obtain consent when UCB is harvested from private bank users, and the results of the above-cited MHLW survey, which found that private banks also fail to provide users with sufficient explanations, cast doubt amidst the absence of relevant laws and regulations as to how much has been suitably explained to UCB donors when they consent to be third-party UCB donors.

We did not determine what sort of explanations institutions handing childbirth give when they deliver UCB to other institutions or store it themselves for research purposes, nor did we determine methods for obtaining consent, as we felt these fell outside the aim of the present study. Future studies must answer these questions and evaluate if there truly is no problem with the current state of affairs in Japan in the absence of rules regarding the harvest or delivery of UCB for research purposes by institutions handling childbirth.

The present study had several limitations. First, the response rate was only 36.7%, which is not at all high. However, the percentages of institutions handling childbirth by type that responded to our survey are roughly consistent with those of Japanese medical treatment facilities overall [29], implying that our results are representative to some extent. Of course, we cannot rule out the effect of non-responder bias. However, the present study can be considered sufficiently significant because this is the first study to determine the status of UCB delivery by Japanese institutions handling childbirth to private banks, other companies, research institutions, and medical treatment facilities. The 3,277 facilities included in this study represent 99.9% of childbirth facilities in Japan. The total number of facilities in Japan is approximately 3,280. Of which 1,084 facilities responded that they handled childbirth. A simple calculation from the actual number of births in 2016 (976,978 births), a year before this study was conducted [30], allowed us to estimate that the facilities included in our study handled a total of 322,879 births. The number of UCBs managed by these facilities can be considered significant. In addition, by determining the status of UCB delivery prior to revision of the APHSCT, we have made it possible to determine the effects of APHSCT via comparisons with post-revision survey results.

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Current status of umbilical cord blood storage and provision to private biobanks by institutions handling childbirth in Japan - BMC Medical Ethics -...

IPS Cell Therapy Comments Off on Current status of umbilical cord blood storage and provision to private biobanks by institutions handling childbirth in Japan – BMC Medical Ethics -… | September 19th, 2022

DUBLIN--(BUSINESS WIRE)--The "Induced Pluripotent Stem Cells Market - Growth, Trends, Covid-19 Impact, and Forecasts (2022 - 2027)" report has been added to ResearchAndMarkets.com's offering.

The Induced Pluripotent Stem Cells Market is projected to register a CAGR of 8.4% during the forecast period (2022 to 2027).

Companies Mentioned

Key Market Trends

The Drug Development Segment is Expected to Hold a Major Market Share in the Induced Pluripotent Stem Cells Market.

By application, the drug development segment holds the major segment in the induced pluripotent stem cell market. Various research studies focusing on drug development studies with induced pluripotent stem cells have been on the rise in recent years.

For instance, an article titled "Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening" published in the International Journal of Molecular Science in October 2020 discussed the broad use of iPSC derived cardiomyocytes for drug development in terms of adverse drug reactions, mechanisms of cardiotoxicity, and the need for efficient drug screening protocols.

Another article published in the Journal of Cells in December 2021 titled "Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform-A Cardiac Perspective" focused on methods to reprogram somatic cells into human induced pluripotent stem cells and the solutions to overcome the immaturity of the human induced pluripotent stem cells derived cardiomyocytes to mimic the structure and physiological properties of adult human cardiomyocytes to accurately model disease and test drug safety. Thus, this increase in the research of induced pluripotent stem cells for drug development and drug modeling is likely to propel the segment's growth over the study period.

Furthermore, as per an article titled "Advancements in Disease Modeling and Drug Discovery Using iPSC-Derived Hepatocyte-like Cells" published in the Multi-Disciplinary Publishing Institute journal of Cells in March 2022, preserved differentiation and physiological function, amenability to genetic manipulation via tools such as CRISPR/Cas9, and availability for high-throughput screening, make induced pluripotent stem cell systems increasingly attractive for both mechanistic studies of disease and the identification of novel therapeutics.

North America is Expected to Hold a Significant Share in the Market and Expected to do Same in the Forecast Period

The rise in the adoption of highly advanced technologies and systems in drug development, toxicity testing, and disease modeling coupled with the growing acceptance of stem cell therapies in the region are some of the major factors driving the market growth in North America.

The United States Food and Drug Administration in March 2022 discussed the development of strategies to improve cell therapy product characterization. The agency focused on the development of improved methods for testing stem cell products to ensure the safety and efficacy of such treatments when used as therapies.

Likewise, in March 2020, the Food and Drug Administration announced that ImStem drug IMS001, which uses AgeX's pluripotent stem cell technology, would be available for the treatment of multiple sclerosis. Similarly, REPROCELL introduced a customized iPSC generation service in December 2020, as well as a new B2C website to promote the "Personal iPS" service. This service prepares and stores an individual's iPSCs for future injury or disease regeneration treatment.

Thus, the increasing necessity for induced pluripotent stem cells coupled with increasing investment in the health care department is known to propel the growth of the market in this region.

Key Topics Covered:

1 INTRODUCTION

2 RESEARCH METHODOLOGY

3 EXECUTIVE SUMMARY

4 MARKET DYNAMICS

4.1 Market Overview

4.2 Market Drivers

4.2.1 Increase in Research and Development Activities in Stem Cells Therapies

4.2.2 Surge in Adoption of Personalized Medicine

4.3 Market Restraints

4.3.1 Lack of Awareness Regarding Stem Cell Therapies

4.3.2 High Cost of Treatment

4.4 Porter's Five Force Analysis

5 MARKET SEGMENTATION

5.1 By Derived Cell Type

5.2 Application

5.3 End User

5.4 Geography

6 COMPETITIVE LANDSCAPE

6.1 Company Profiles

7 MARKET OPPORTUNITIES AND FUTURE TRENDS

For more information about this report visit https://www.researchandmarkets.com/r/ylzwhr

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Global Induced Pluripotent Stem Cells Market (2022 to 2027) - Growth, Trends, Covid-19 Impact and Forecasts - ResearchAndMarkets.com - Business Wire

IPS Cell Therapy Comments Off on Global Induced Pluripotent Stem Cells Market (2022 to 2027) – Growth, Trends, Covid-19 Impact and Forecasts – ResearchAndMarkets.com – Business Wire | September 11th, 2022

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Clinical translation of stem cell therapy for spinal cord injury still premature: results from a single-arm meta-analysis based on 62 clinical trials...

IPS Cell Therapy Comments Off on Clinical translation of stem cell therapy for spinal cord injury still premature: results from a single-arm meta-analysis based on 62 clinical trials… | September 11th, 2022

Correlation between PSC differentiation potential and level of CHD7 expression

The potential to differentiate is a critical feature of PSCs used for cell transplantation therapy. Therefore, establishing an assay to evaluate differentiation potential is essential for the maintenance culture of PSCs. EB formation in EB assays is used as a minimum requirement to demonstrate differentiation potential, although EB formation assays may not necessarily guarantee the ability to differentiate into the designated target cells without bias. We used ESC H9 cells in the majority of experiments shown in this study as a representative PSC cell line to minimize the concern of clonal variance in PSC clones that is typically observed among iPSC clones generated from somatic cells with various genetic and epigenetic profiles and with versatile reprogramming methods. H9 cells cultured on VTN-Ncoated dishes with Es8 (Thermo Fisher) medium formed a considerable number of EBs; however, the number of EBs was reduced considerably after the cells were transferred to RFF2 medium and cultured for 15days (3days/passage5). The cells showed an ability to form a comparable number of EBs again when transferred to Es8 and cultured for 24days (3days/passage8 passages), consistent with our previous report using ESC KhES-1 and iPSC PFX#91. The expression level of CHD7 determined by flow cytometry and the copy number of CHD7 measured by ddPCR was higher in cells cultured with Es8 than in cells cultured with RFF2 (Fig.1A). We noted that the cell number scored at day 3 was approximately 3 times higher in cells cultured with Es8 than with RFF2. There was a positive relationship between cell growth rate, CHD7 expression level, and differentiation potential when H9 cells were cultured on VTN-Ncoated dishes and passaged in a single-cell suspension.

The differentiation potential of cells in culture can be altered by culture medium. (A) H9 cells cultured with Essential 8 (Es8) medium on vitronectin-N (VTN)coated dishes were transferred to RFF2 medium, cultured for 15days (3days/passage5 passages), transferred again to Es8 medium, cultured 24days (3days/passage8 passages), and then transferred again to RFF2 medium. Photos of cells in designated culture conditions, with the cell number scored at day 3 after seeding 1.0105 cells (left panels); flow cytometric analysis of CHD7, CHD7 copy numbers from 5ng total RNA at day 3 (middle panels); and photographs of EBs formed by day 14 from cells in each culture condition and numbers of EBs formed (right panels). The results are representative of three independent experiments. (B) H9 cells were cultured either with Es8 or RFF2 on VTN-Ncoated dishes. The loci of copy number variants (CNVs) detected when cells were cultured with Es8 medium (left panels) or RFF2 medium (right panels) are shown. CHD7 expression was determined by flow cytometry (mean values are shown), and CHD7 copy numbers were determined by digital droplet PCR in cells cultured with Es8 or RFF2 medium.

We next explored the mechanisms through which cells had altered CHD7 expression levels and the ability to form EBs by simply changing the culture medium. There were at least two possible explanations for this mechanism. First, cells in culture might exhibit alterations in both CHD7 expression and the resultant differentiation potential because of signals initiated and mediated by certain factors in the medium. Alternatively, CHD7 expression levels might be genetically and epigenetically predetermined in individual cells and might not be regulated or changed by signals triggered by factors in the culture medium. In the latter case, CHD7 expression levels in cultured cells might change if different dominant cell populations were selected based on a growth advantage in a new culture medium. To evaluate these possible mechanisms, cells in the culture were marked by their CNVs so that changes in the dominant cell population could be detected by comparing CNV profiles. H9 cells cultured with Es8 medium were transferred to RFF2 medium and then were placed back in Es8 medium, and the CNV profiles of H9 cells were examined and compared. Notably, the CNV profiles of cells cultured with Es8 medium included CNVs at loci 4q22.1, 8q23.1, 16p11.2, and Xq26.1, whereas cells cultured with RFF2 medium had CNVs at none of these loci. Additionally, cells cultured with RFF2 medium contained CNVs at the specific locus 14q32.33, and these CNVs were not detected in cells cultured with Es8 medium, indicating that the cell population cultured with Es8 medium was different from that cultured with RFF2 medium (Fig.1B). This observation led us to explore the mechanisms through which certain cell populations could be selected to expand under specific culture conditions.

Next, we explored the impact of cell culture medium on the metabolic systems of cultured cells. The major metabolic pathway used by PSCs and cancer cells is the glycolytic pathway7, which is coupled with suppression of mitochondrial activity, as reflected by a low mitochondrial membrane potential (M) and reduced ROS in the mitochondria8,9. We found that the majority of cells cultured with Es8 medium did not show marked ROX staining, which was used to detect ROS produced by mitochondrial activity; the exception was that cells along the rims of colonies did show ROX staining. Furthermore, JC-1 assays showed a suppression of mitochondrial membrane voltage, suggesting that there was no marked mitochondrial activity by day 3 of culture (Fig.2A). In contrast, cells cultured with RFF2 showed marked ROX staining in most cells and an activated mitochondrial membrane potential by the JC-1 assays, suggesting activated mitochondrial function in cells cultured with RFF2 (Fig.2A). RFF2 medium contained high concentrations (approximately 23mg/mL) of protein and various amino acids in addition to moderately high glucose (2.52g/L), which could support mitochondrial function. However, Es8 medium contained high glucose (3.1g/L) and a limited amount of amino acids. Thus, Es8 medium could support the glycolytic pathway and at the same time limit the activation of mitochondrial function. The suppressed mitochondrial membrane voltage of cells cultured with Es8 medium supported this idea. There was a reciprocal relationship between the expression of CHD7 and mitochondrial function when cells were maintained in an undifferentiated state (Fig.2A). Metabolic analysis showed that the RFF2 culture medium contained malate and citrate as a result of activation of the tricarboxylic acid cycle in cells, whereas the Es8 culture medium did not (Fig.2B), consistent with the above argument. Furthermore, 2-aminoadipic acid (2-AAA) was detected in the RFF2 medium but not in the Es8 medium (Fig.2B), indicating that the kynurenine catabolic pathway, which leads to loss of an undifferentiated state and initiation of ectoderm differentiation6, was activated in cells cultured with RFF2. This observation suggested that some cells cultured with RFF2 exhibited activated mitochondrial function and underwent spontaneous differentiation, but could not be maintained in RFF2 as this medium lacked the factors necessary to support differentiated cells, and therefore these cells died. Thus, only undifferentiated cells with mitochondrial activation below the permissible level not to undergo differentiation could be cultured and maintained with the RFF2 medium. A positive correlation between the activation of mitochondrial membrane voltage and the initiation of differentiation, as suggested by the secretion of 2-AAA, was observed during the culture of cells with RFF2. This observation was supported by additional experiments; namely, H9 cells cultured with Es6 medium depleted of basic fibroblast growth factor and transforming growth factor 1 compared with Es8 medium showed both an initiation of ectodermal differentiation, as demonstrated by gene expression profiling using RT-qPCR (Fig.2C, Fig. S1), and an elevated mitochondrial membrane voltage (Fig.2A,C). Thus, there is evidence that the activation of mitochondrial function is coupled with the initiation of differentiation processes. Next, we examined the impact of elevated CHD7 expression levels and the induction of spontaneous differentiation by introducing mCHD7 into undifferentiated cells.

Activation of mitochondrial function is coupled with differentiation. (A) Morphology, CellROX (ROX) immunostaining, CHD7 copy numbers, and mitochondrial membrane voltage (JC-1 assays) in cells cultured with Es8 medium on VTN-Ncoated dishes (Es8/VTN) for 3days (left panels) or with RFF2 medium on VTN-Ncoated dishes (RFF2/VTN) for 3days (right panels) are shown. Mitochondrial membrane voltage was assessed by subtracting baseline electrons (after depolarization) from total electrons (red circle). The percentage of each fraction in the scatter plot of JC-1 assays is shown. (B) H9 cells were cultured with Es8 or RFF2 medium, and culture medium was collected and replaced with fresh medium every day for 3days. 2-Aminoadipic acid (2-AAA), malate, and citrate levels in culture medium were measured using LCMS/MS. The measured values were standardized as the mean area ratio/cell/h for 3days. The average values (n=3) with error bars (SD) are shown in the bar graphs. The results of three independent experiments are shown. (C) Morphology, ROX staining, mitochondrial membrane voltage (JC-1 assays; red circle), and gene expression profiles (RT-qPCR score card panels) of H9 cells cultured with Es8 medium on VTN-Ncoated dishes on day 5 (left panel: starting material for differentiation by Es6 medium) and Es6 medium on VTN-Ncoated dishes on day 5 are shown (right panel). The interpretation of gene expression levels by RT-qPCR is shown in the attached table. The results of three independent experiments are shown.

There was a positive correlation between the level of CHD7 expression in undifferentiated cells and the differentiation potential manifested by the number of EBs formed in the EB formation assay (Fig.1A). Interestingly, mCHD7 induced differentiation of the three germ layers simultaneously, as determined by RT-qPCR in cells cultured with both Es8 and RFF2 media (Fig.3A, Fig. S2), suggesting a positive role of CHD7 in both endodermal and mesodermal differentiation processes as well as in ectodermal development. Furthermore, this suggested that there is an upper permissible level of CHD7 being in an undifferentiated state. Es8 and RFF2 media are designed to support the proliferation of undifferentiated cells, not differentiated cells, and cells that forced to differentiate following the introduction of mCHD7, could not be maintained in these culture media. Consequently, the number of cells to form EBs was markedly reduced after introduction of mCHD7 (Fig.3A). Moreover, the introduction of siCHD7 reduced the differentiation potential of cells cultured with Es8, as reflected by the marked reduction in the number of EBs formed (Fig.3A). The introduction of siCHD7 to cells cultured with RFF2 further reduced the level of CHD7 and naturally led to no or few EBs being generated. These results provided evidence for the observation in Fig.1A, demonstrating that the differentiation potential of undifferentiated cells correlated with CHD7 expression.

CHD7 expression affected the differentiation potential and growth of undifferentiated cells. (A) H9 cells cultured with Es8 on VTN-Ncoated dishes (Es8/VTN, left panels) or with RFF2 on VTN-Ncoated dishes (RFF2/VTN, right panels) were transfected with mock (control), mCHD7, or siCHD7. The morphology, CHD7 copy numbers, gene expression profiles (RT-qPCR), EB morphology, and EB numbers formed at day 14 under different culture conditions are shown. The representative results of three independent experiments are shown. (B) CHD7 expression in H9 cells determined by flow cytometry after cells were transferred from RFF2 to Es8 on VTN-Ncoated dishes at passage 0 (P0), P5, and P7. Cells were cultured for 3days between passages. (C) Fold increase of H9 cells after 48h (upper panel) and CHD7 expression, as determined by RT-qPCR, after transfection of H9 cells with various doses of siCHD7 (lower panel). The average values (n=3) with error bars (SD) are shown in the bar graphs. Representative data from three independent experiments are shown.

It is interesting to note that both the increased expression of mCHD7 and the activation of mitochondrial function induced differentiation. Therefore, there must be a reciprocal relationship between these events in cells in an undifferentiated state. In other words, cells with activated mitochondrial function need to express a limited level of CHD7 to grow in an undifferentiated state at the expense of having a reduced differentiation potential, whereas cells with suppressed mitochondrial function could have relatively high CHD7 levels, enabling these undifferentiated cells to retain differentiation potential. The level of CHD7 that can ensure the differentiation potential of cells varied across cell lines and culture methods, therefore we cannot determine a universal cutoff value for every cell line. However, H9 cells with a CHD7 copy number of less than 2000 copies/5ng total RNA showed a limited differentiation potential when cultured on VTN-Ncoated dishes (Figs. 1B, 2A, 3A).

In the previous sections, we have shown (1) the introduction of mCHD7 induced spontaneous differentiation (Fig.3A), (2) the differentiation process was coupled with the activation of mitochondrial function (Fig.2C), and (3) there was a reciprocal relationship between the CHD7 expression level and the degree of mitochondrial function in undifferentiated cells (Fig.2A). The question is how the CHD7 expression and the degree of mitochondrial function corelated each other. We showed culture medium selected a cell population to grow (Fig.1B), and the activation of mitochondria of cells in culture is directly affected by the formula of culture medium (Fig.2A). While, we could not demonstrate the relationship between formula of the medium and the expression of CHD7, rather the CHD7 expression level in cells as assessed by flow cytometry showed a broad coefficient of variation (CV) just after the culture medium was changed from RFF2 to Es8 (Fig.3B, P0). Then, the level of CHD7 expression came to converge at the highest level during the culture (Fig.3B, P5 and P7). This result suggests that cells with a higher CHD7 expression have a growth advantage and become dominant during the culture. This presumption was manifested by the CHD7 knockdown experiment using siCHD7. This experiment indicated that the level of CHD7 was positively correlated with cell proliferation potential (Fig.3C) and cells with a higher CHD7 expression became dominant due to a growth advantage after a couple of passages. This would explain the observation that the expression of CHD7 reached its highest level during the late passages, as shown in Fig.3B (P7).

In addition to the differentiation potential, the retention of self-renewal potential is a key feature of PSCs. PSCs require cell-to-cell contact to grow and, therefore, PSCs need to form colonies. For the clinical application of PSCs, we must focus on an animal-free cell culture system. Therefore, synthetic ECM was used as the dish-coating material based on regulatory considerations. However, cells on the rims of the 2-dimensional (2-D) colonies lack the signals triggered by cell-to-cell contact at one open end, which is in sharp contrast with the majority of cells located in the middle of the colony that are surrounded by other cells along their cell membrane without interruption. Cells along the rim of the colony have an uneven distribution of molecules and ion flux related to the cell-to-cell contact-mediated signals and undergo uneven segregation in mitosis. This, then, results in a break of the self-renewal state where two identical daughter cells are generated from a mother cell, triggering spontaneous differentiation10,11,12. Indeed, cells on the rims of the colonies were positively stained with anti-superoxide dismutase 2 (SOD2) antibodies (Fig.4A). SOD2 is an enzyme that belongs to the Fe/Mn superoxide dismutase family, which scavenges excess ROS generated as a result of mitochondrial activation. SOD2 gene expression in H9 cells in the culture showed that these cells committed ectoderm and mesoderm differentiation (Fig.4A). Consequently, the population of undifferentiated cells would decrease if the spontaneously differentiated cells were not properly removed from the culture. Notably, the percentage of SOD2-positive cells (4.9%) on day 5 of culture with Es8/L511 was reduced after cells were seeded in single-cell suspensions on VTN-N(0.9%), L521-(2.6%), or L511-(2.8%) coated dishes after 30h (Fig.4B). This suggests that the ability of cells to adhere to the ECM was reduced in differentiated cells compared with undifferentiated cells, and the cell-binding ability of L511 or L521 for differentiated cells was higher than that of VTN-N. Gene expression profiles showed that cells cultured on L511 or L521 were committed to ectoderm and mesoderm differentiation (Fig.4B). Thus, by exploiting the reduced cell adhesion properties of differentiated cells and the less potent cell-binding properties of VTN-N, differentiated cells could be effectively eliminated from the culture at a single-cell level by seeding cells in a single-cell suspension at each passage.

The removal of differentiated cells by seeding on a less adhesive material. (A) H9 cells cultured with Es8 on L511-coated dishes for 5days were stained with anti-SOD2 antibodies (upper left panel), and SOD2-positive (red dots) and SOD2-negative (black dots) cells were sorted (upper right panel) to examine the ectodermal or mesodermal gene expression patterns of each population by RT-qPCR (bottom panel). (B) H9 cells cultured with the conditions described in panel A (total 2.1106 cells, 4.9% SOD2-positive cells) were collected and 5.0104 cells from them were seeded as single-cell suspensions either on L511-, L521-, or VTN-Ncoated dishes and cultured for 30h with Es8. The total cell numbers harvested and the percentages of SOD2-positive cells under different culture conditions are shown. The ectodermal or mesodermal gene expression levels of cells cultured under relevant conditions as determined by RT-qPCR are shown in the lower bar graph. The interpretation of gene expression levels determined by RT-qPCR is shown in the attached table. Representative results from three independent experiments are shown.

In previous sections, we showed data using ESC H9 cells as the standard control PSC clone to avoid possible arguments about iPSC clones having diverse genetic and epigenetic backgrounds. Therefore, there is a strong need to standardize iPSC clones to develop iPSC-based cell therapy. In the previous section, we showed that the differentiation potential of even ESC H9 cells, which have relatively homogenous genetic and epigenetic profiles, could be altered by culture medium (Fig.1) and there is a possibility that we can improve the differentiation potential by optimizing culture conditions. Optimized culture conditions may include the selection of an appropriate culture medium that supports the glycolytic pathway, the seeding of cells as single-cell suspensions during passaging, and the culture of cells on an ECM substrate with a relatively weak cell-binding capacity, such as VTN-N, to minimize the inclusion of differentiated cells in undifferentiated cell cultures and to maintain the self-renewal population for the expansion of cell clones. To verify that culture conditions improved the differentiation potential of established iPSC clones, we cultured the iPSC clones 253G113, 201B75, PFX#9, and SHh#24 and the ESC clone H9 (control) with iPSC medium4 or mTeSR1 and maintained them on feeder cells or on L511- or L521-coated dishes that were transferred to Es8 medium, cultured on VTN-Ncoated dishes, and passaged as single-cell suspensions. The CHD7 expression profile by flow cytometry and the number of EBs formed before and after the transition to Es8/VTN-N culture were measured. Notably, increased levels of CHD7 expression by flow cytometry before and after recloning (Fig.5A) may be a good index for an improved differentiation potential of cells, as manifested by an increase in the number of EBs formed (Fig.5B). The convergence of CHD7 expression by flow cytometry (Fig.5A) may represent a decreased variance in the differentiation potential among iPSCs in a given culture.

Recloning of cells with differentiation potential based on culture conditions. (A) iPSC clones (201B7, PFX#9, SHh#2, or 253G1 cells) or ESC clones (H9 cells) were cultured either on feeder cells or on L511- or L521-coated dishes with iPSC or mTeSR1 medium. Clones were then transferred to Es8 medium and cultured on VTN-Ncoated dishes. The mean and convergence of CHD7 expression of cell clones was determined by flow cytometry before (gray histogram) and after (red histogram) changing culture conditions. Representative results from three independent experiments are shown. (B) Flow cytometric analysis of cell clones for the mean and coefficient of variation (CV) measured before (circle) and after (square) changing culture conditions are plotted on the left panel and the differentiation potential before and after changing the culture conditions was assessed by the number of EBs formed and is shown on the right panel. The data set shown in (B) was generated from the same samples shown in (A).

Although we cannot alter the genetic background of individual cells by changing culture conditions, a cell population with a higher differentiation potential could be selected to grow, or be recloned, by culture conditions that support the glycolytic pathway and by eliminating spontaneously differentiated cells by seeding on an ECM with a less potent cell-binding capability, thus exploiting their reduced adhesive properties. This could also reduce the variability in differentiation potential, especially among iPSC clones.

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When coronary arteries are blocked, starving the heart of blood, there are good medications and treatments to deploy, from statins to stents. Not so for heart failure, the leading factor involved in heart disease, the top cause of death worldwide.

Its whats on death certificates, said cardiologist Christine Seidman.

Seidman has long been interested in heart muscle disorders and their genetic drivers. She studies heart failure and other conditions that affect the myocardium the muscular tissue of the heart not the blood vessels where atherosclerosis and heart attacks come from, although their consequences are also felt in the myocardium, including heart failure.

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With her colleagues at Brigham and Womens Hospital and Harvard Medical School, she and a long list of international collaborators have been exploring the genetic underpinnings of heart failure. Based on experiments deploying a new technique called single-nucleus RNA sequencing on samples from heart patients, on Thursday they reported in Science their discovery of how genotypes change the way the heart functions.

Their work raises the possibility that some of the molecular pathways that lead to heart failure could be precisely targeted, in contrast to treating heart failure as a disease with only one final outcome.

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Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting, she said. To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

Seidman talked with STAT about the research, including how snRNAseq solves the smoothie problem, and what it might mean for patients. The conversation has been edited for clarity and brevity.

What happens in heart failure?

The heart becomes misshapen in one of two ways. It either becomes hypertrophied, where the walls of heart muscle become thickened and the volume within the heart is diminished, in what we call hypertrophic cardiomyopathy. Or it becomes dilated, when the volume in the heart is expanded and the walls become stretched. I think of it as an overinflated balloon, and that is called dilated cardiomyopathy.

Hypertrophy and dilatation are known to cause the heart over time to have profoundly diminished functional capacity. And clinically, we call that heart failure, much more commonly arising from dilated cardiomyopathy.

What does it feel like to patients?

When we see patients clinically, theyre short of breath, they have fluid retention. When we look at their hearts, we see that the pump function is diminished. That has led to a hypothesis of heart failure as sort of the end stage of many different disorders, but eventually the heart walks down a final common pathway. Then you need a transplant or a left ventricular assist device, or youre going to die prematurely.

What can be done?

Heart failure is a truly devastating condition, and it can arise early in life, in middle age, and in older people. There is no treatment for it, no cure for it, except cardiac transplantation, of course, which provides a whole host of other problems.

How did you approach this problem?

One of the questions we wanted to answer is, are there signals that we can discern that say there are different pathways and there are molecules that are functioning in those pathways that ultimately converge for failure, but through different strategies of your heart?

We treat every patient with heart failure with diuretics. We give them a series of different medications to reduce the pressure against which the heart has to contract. Im clinically a cardiologist, but molecularly Im a geneticist, so it doesnt make sense. If your house is falling down because the bricks are sticking together or if its falling down because the roof leaks and the water is pooling, you do things differently.

Tell me how you used single-cell RNA sequencing to learn more.

Looking at RNA molecules gives us a snapshot of how much a gene is active or inactive at a particular time point. Until recently, we couldnt do that in the heart because the approach had been to take heart tissue, grind it all up, and look at the RNAs that are up or down. But that gives you what we call a smoothie: Its all the different component cells those strawberries, blueberries, bananas mixed together.

But theres a technology now called single-cell RNA sequencing. And that says, what are the RNAs that are up or down in the cardiomyocytes as compared to the smooth muscle cells, as compared to the fibroblasts, all of which are in the cells? You get a much more precise look at whats changing in a different cell type. And thats the approach that we use, because cardiomyocytes [the cells in the heart that make it contract] are very large. Theyre at least three times bigger than other cells. We cant capture the single cell it literally does not fit through the microfluidic device. And so we sequenced the nuclei, which is where the RNA emanates from.

What did you find?

There were some similarities, but what was remarkable was the degree of differences that we saw in cardiomyocytes, in endothelial cells, in fibroblasts. Theres a signature thats telling us I walked down this pathway as compared to a different one that caused the heart to fail, but through activation or lack of activation of different signals along the way.

And that to me is the excitement, because if we can say that, we can then go back and say, OK, what happens if we were to have tweaked the pathway in this genotype and a different pathway in a different genotype? Thats really what precision therapy could be about, and thats where we aim to get to.

Whats the next step?

It may be that several genotypes will have more similarities as compared to other genotypes. But understanding that, I think, will allow us to test in experimental models, largely in mice, but increasingly in cellular models of disease, in iPS [induced pluripotent stem] cells that we can now begin to use molecular technologies to silence a pathway and see what that does to the cardiomyocytes, or silence the fibroblast molecule and see what that does in that particular genotype.

To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

What might this mean for patients?

If we knew that an intervention would make a difference thats where the experiments are we would intervene when we saw manifestations of disease. So the reason I can tell you with confidence that certain genes cause dilated cardiomyopathy is theres a long time between the onset of that expansion of the ventricle until you develop heart failure. So theres years for us to be able to stop it in its tracks or potentially revert the pathology, if we can do that.

What else can you say?

I would be foolish not to mention the genetic cause of dilated cardiomyopathy. Ultimately, if you know the genetic cause of dilated cardiomyopathy, this is where gene therapy may be the ultimate cure. Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting.

My colleagues have estimated that approximately 1 in 250 to 1 in 500 people may have an important genetic driver of heart muscle disease, cardiomyopathy. Thats a huge number, but not all of them will progress to heart failure, thank goodness. Around the world, there are 23 million people with heart failure. Its what ends up on most peoples death certificate. It is the most common cause of death.

Its a huge, huge burden. And there really is no cure for it except transplantation. We dont have a reparative capacity, so were going to have to know a cause and be able to intervene precisely for that cause.

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Creative Biolabs stem cell platform offers expertise in the generation, bioprocess scale-up, and differentiation of iPSCs.

New York, USA August 3, 2022 Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from somatic cells. iPSC technology has evolved rapidly since its inception in 2006 and has been widely used for disease modeling.

The global iPSC market is expected to grow from $2431.2 million in 2021 to $2640.80 million in 2022 at a compound annual growth rate (CAGR) of 8.6%. Meanwhile, the market is expected to reach $3571.48 million in 2026 at a CAGR of 7.8%, according to the Report Linker.

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With years of exploration in the iPSC development, Creative Biolabs is dedicated to providing helpful iPSC culture services, including maintenance of iPSC, 3D culture of iPSC, as well as scale-up of iPSC culture.

Researchers at Creative Biolabs have built two unique systems for iPSCs culture, which are the feeder-dependent culture system and the feeder-free culture system. In order to break the bottleneck for mass production of high-quality iPSCs, Creative Biolabs has built a 3D culture system for iPSC expansion and differentiation based on a thermoreversible hydrogel. The 3D culture system enables a long-term and serial expansion of multiple human iPSC lines via a mild process. With these wonderful advantages, the 3D culture system may be useful at various scales, from basic biological research to clinical trials.

Moreover, the use of bioreactor systems has greatly improved the development of dynamic suspension culture. Bioreactor systems can promote the control of iPSC aggregation, avoid the formation of gradients, and improve the mass transfer, thus leading to higher cell density.

With the advanced iPSC development platform, Creative Biolabs offers high-quality iPSC genome editing services. Nowadays, the application of custom-engineered sequence-specific nucleases enables genetic changes in human cells to be easily accessed with much greater efficiency and precision, such as CRISPR/Cas9 and TALEN. iPSC genome editing services at Creative Biolabs can help achieve the following goals:

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With professional scientists and years of experience, Creative Biolabs provides high-quality products and services in the field of stem cell therapy development for customers all over the world.

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image:Differentiation of pluripotent stem cells (PSCs) is regulated through a methionine-mediated mechanism, which has now been pinpointed by Tokyo Tech researchers. They have revealed that zinc (Zn) plays a crucial role in PSC potentiation. They used these insights to design a protocol to convert PSCs into insulin-producing pancreatic cellsa high-potential diabetes therapy. view more

Credit: Prof. Shoen Kume from Tokyo Institute of Technology

Differentiation of pluripotent stem cells (PSCs) is regulated through a methionine-mediated mechanism, which has now been pinpointed by Tokyo Tech researchers. They have revealed that zinc (Zn) plays a crucial role in PSC potentiation. They used these insights to design a protocol to convert PSCs into insulin-producing pancreatic cellsa high-potential diabetes therapy.

Stem cell research has gained a lot of attention in the world of medical therapeutics. Pluripotent stem cells (PSCs) can self-renew and transform into different types of cells in the body via a process called differentiation. These cells have manifold applications, such as disease modeling, drug discovery, and cell replacement therapy.

One area of focus in PSC research is diabetes treatments. A common characteristic of diabetes is having ineffective or overworked pancreatic cellscells that produce insulin. Controlling the differentiation of PSCs to produce cells is one of the major goals of research in the field. Previous studies have shown that methionine, an amino acid, plays a major role in the differentiation of PSCs. But the precise mechanism behind this has been, thus far, unknown.

To find the missing piece of this puzzle, a team of researchers from Japan, led by Prof. Shoen Kume from Tokyo Institute of Technology (Tokyo Tech), delved deeper into the methionine-mediated regulation of PSC pluripotency. In a recent study published in Cell Reports, the researchers revealed that cellular zinc (Zn) content played a crucial role in stem cell differentiation. Prof. Kume explains, Earlier research in the area has shown that if we culture PSCs in a medium which is deficient in methionine, it leads to a reduction in intracellular S-adenosyl methionine or SAM, which renders PSCs in a state of potentiated differentiation. But our study further identified that zinc (Zn) is a downstream target of methionine metabolism and it can potentiate pluripotency in undifferentiated PSCs.

In this study, the research team first cultured PSCs in a methionine-deprived environment. They found that methionine-deprivation not only reduced the intracellular protein-bound Zn levels in cells, but that it also upregulated SLC30A1, a gene that produces an important Zn transport protein.

The team then cultured hiPSCs under low Zn concentrations. They discovered that a Zn-deprived medium partially mimicked methionine deprivation and led to a decrease in cell growth and an increase in potentiated differentiation. They also found that the Zn deprived state also altered the methionine metabolism profile and eliminated undifferentiated hiPSCs. These results indicated that methionine deprivation-induced differentiation takes place by lowering the Zn content in cells.

Using the insights, the team then developed a methodology for generating insulin-producing pancreatic cells. cell transplantation is a promising treatment for diabetes, but there is a paucity of donor cells for the treatment, as well as immune-related complications that can arise from this treatment. Using PSCs to produce genetically-matching cells is a way to overcome this, explains Prof. Kume.

These findings indicate a link between Zn mobilization and methionine-induced potentiation of PSCs and provide clear a direction for future research in the field of stem cell therapies.

Related Information

Today's Stem Cell Special: Small Intestine on a Plate! https://www.titech.ac.jp/english/news/2021/048927

A Ferry Protein in the Pancreas Protects It from the Stress Induced by a High-Fat Diet | Tokyo Tech Newshttps://www.titech.ac.jp/english/news/2020/047867.html

Move over Akita: Introducing 'Kuma Mutant' Mice for Islet Transplantation Researchhttps://www.titech.ac.jp/english/news/2020/047462

Shoen Kume - Towards a new therapy for diabetes - Regenerating pancreas from ES and iPS cellshttps://www.titech.ac.jp/english/public-relations/research/stories/faces37-kume

Kume &Shiraki Lab.http://www.stem.bio.titech.ac.jp/index.html

About Tokyo Institute of Technology

Tokyo Tech stands at the forefront of research and higher education as the leading university for science and technology in Japan. Tokyo Tech researchers excel in fields ranging from materials science to biology, computer science, and physics. Founded in 1881, Tokyo Tech hosts over 10,000 undergraduate and graduate students per year, who develop into scientific leaders and some of the most sought-after engineers in the industry. Embodying the Japanese philosophy of monotsukuri, meaning technical ingenuity and innovation, the Tokyo Tech community strives to contribute to society through high-impact research.

https://www.titech.ac.jp/english/

Experimental study

Cells

Methionine metabolism regulates pluripotent stem cell pluripotency and differentiation through zinc mobilization

19-Jul-2022

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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The zinc link: Unraveling the mechanism of methionine-mediated pluripotency regulation - EurekAlert

IPS Cell Therapy Comments Off on The zinc link: Unraveling the mechanism of methionine-mediated pluripotency regulation – EurekAlert | July 25th, 2022

In this free webinar, learn how live cell metabolic analysis paves the way not only for metabolic research, but also the manufacturing of significant cell and gene therapy (CGT) products. Attendees will learn how glycolysis metabolic process can be measured directly through the continuous measuring of glucose and lactate amounts in the culture media using electrochemical sensors which provides new scientific insights. The featured speakers will discuss how continuous monitoring is effectively utilized for the process development stage of CGT products and quality control during the manufacturing stage of CGT products. The speakers will also discuss how glucose and lactate can be monitored in the traditional lab environment using conventional 24-well plate and CO2 incubators without any sampling.

TORONTO (PRWEB) July 12, 2022

Among the various biological functions cells carry out to maintain life, metabolism is the key activity used to process nutrient molecules. It is also closely associated with cell proliferation and differentiation. Cell metabolic analysis would be very helpful to monitor these activities.

In the field of cancer immunotherapy such as CAR T and TCR-T therapy, stem cell research including embryonic stem (ES) and induced pluripotent stem (iPS) cells and commercial cell and gene therapy (CGT) manufacturing process development investigating and understanding the metabolic activities of cells are critical. To meet this need in the field, PHC Corporation will launch a continuous metabolic analyzer which leads to real-time visualization of the metabolic condition of living cells. This development will encourage new discoveries that have not been seen in previous studies.

Register for this webinar to learn how live cell metabolic analysis paves the way not only for metabolic research, but also the manufacturing of significant CGT products.

Join experts from PHC Corporation of North America, Ryosuke Takahashi, PhD VP, Cell and Gene Therapy Business; and Kenan Moss, Application Specialist, for the live webinar on Tuesday, July 26, 2022, at 11am EDT (4pm BST).

For more information, or to register for this event, visit Live Cell Metabolic Analysis Paving the Way for Metabolic Research and Cell & Gene Therapy.

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For the original version on PRWeb visit: https://www.prweb.com/releases/live_cell_metabolic_analysis_paving_the_way_for_metabolic_research_and_cell_gene_therapy_upcoming_webinar_hosted_by_xtalks/prweb18784251.htm

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Live Cell Metabolic Analysis Paving the Way for Metabolic Research and Cell & Gene Therapy, Upcoming Webinar Hosted by Xtalks - Benzinga

IPS Cell Therapy Comments Off on Live Cell Metabolic Analysis Paving the Way for Metabolic Research and Cell & Gene Therapy, Upcoming Webinar Hosted by Xtalks – Benzinga | July 16th, 2022

Introduction

Stem cells are highly specialized cell types with an impressive ability to self-renew, able to transform into one or even more specific cell types that play a significant role in the regulation and tissue healing process.17 To self-renew, a stem divides into two identical daughter stem cells and a progenitor cell and the embryonic and adult cells contain stem cells.1,2,8

Curing patients with serious medical conditions has been the focus of all disciplines of medical research for many years. Stem cell treatment has evolved into a highly exciting and progressed field of scientific research. Major advances have recently been introduced in fundamental and translational stem-cell-based treatment studies. As stem cell research progressed, many therapeutic options were investigated. The development of therapeutic procedures has sparked a great deal of interest.1,9 Humanity has known for many years that it is possible to regenerate lost tissue. Recently, the regenerative medicine research has taken hold, defying the tremendous scientific advances in the molecular biology sciences only. Technological advances provide limitless opportunities for transformational and potentially restorative therapies for many of humanitys most illnesses. A variety of human organs have successfully yielded stem cells. Besides this, the cell therapy is rapidly bringing good advancements in the healthcare system, intending to restore and possibly replace injured tissue, as well as organs, and ultimately restore the functional capacity of the body.2,10,11

The stem cells can be obtained from various sources of Adult (Adult body tissues), Embryonic (Embryos), Mesenchyma (Connective tissue or stroma), and Induced pluripotent stem [ips] cells (Skin cells or tissue-specific cells).3,68,1215

Due to various stem cells cellular characteristics, the therapeutic clinical possibilities of stem-cell-based treatment are considered promising. These cells can regrow and restore various types of body tissues, for this reason, they are recognized as precursor cells to all kinds of cells.15 The following are the distinguishing features: 1. Self-renewal- Divide without distinction to generate an infinite supply, 2. Multi-potency- One mature cell may distinguish more than one, 3. Pluripotency- Create all sorts of cells except for embryonic membrane cells, 4. Toti- potency- Produce various sorts of cells, including embryonic stem cells.1,2,6,7,16

Stem cells are essential human cells that really can self-renew and make a distinction into particular mature cell types.3,6 The different types of stem cells are embryonic, induced pluripotent, and adult kind of cell types. They all share the important feature of self-renewal, and the ability to discern themselves. It should be mentioned that, the stem cells are not homogeneous, but instead appear in a progressive order. Totipotent stem cells are the most basic and immature stem cells. The above cells can form a complete embryo and also extra-embryonic tissue. This one-of-a-kind efficiency is only present for a short period, starting with ovum development and completing whenever the embryo achieves the 4 to 8 cell phases. Having followed that, cells that divide until they approach the blastocyst, about which point they end up losing their totipotency and acquire a pluripotent character trait, at which cells can only distinguish through each embryonic germ stack. After a few divisions, the pluripotency character trait starts to fade and the distinguishing ability has become more lineage constrained, where its cells are becoming multipotent, indicating they could only transform into the cells connected to a cell or tissue of origin.10 Many researchers believe that adult stem cells should be used in stem cell therapies.6,17

The stem cells can be transformed into a wide range of specialized functional cell types.3,18 In response to injury or maturation, those same stem cells can propagate in massive quantities.19 Adult, embryonic, and induced pluripotent stem cells are examples of stem cell-based therapies.14,15,1921 The stem cells, due to their capability to distinguish the specific cell types requisite for a diseased tissue regeneration, can provide an effective solution, while tissue and organ transplantation are considered necessary.10 The sophistication of stem cell-based treatment interventions, on the other hand, probably leads researchers to seek stable, credible, and readily available stem cell sources capable of converting into numerous lineages. As an outcome, it is critical to exercise caution when selecting the type of stem cells to be used in therapeutic trials.12,14,22

Only with the explosive growth of basic stem cell research in recent years, the comparatively recent study sector of Translational Research had also grown exponentially, starting to build on major research knowledge and insight to advance new therapies. Once the necessary regulatory clearances have been obtained, the clinical translation process can start. Translational research is important because it acts as a filtration system, ensuring that only safe and effective therapeutic approaches start making it to the clinic.23 Recent research illustrating, the successful application of stem cell transplantation to patient populations suggests that, such restorative approaches have been used to address a wide variety of complicated ailments of future concerns.19,24

Currently, clinical trials are available for a variety of stem cell-based treatments based on adult stem cells. To date, the WHO International Clinical Experiments Registration process has recorded more than 3000 experiments involved based on adult stem cells. Furthermore, preliminary trials involving novel and intriguing pluripotent stem cell therapies have been registered. These studies findings will assist the ability to comprehend and the timeframes required to obtain effective treatments and it will contribute to a better knowledge of the different disorders or abnormalities.10

The role of stem cells in modern medicine is vital, both for their widespread application in basic research and for the opportunities they provide for developing new therapeutic strategies in clinical practice.6,16 In recent times, the number of studies involving stem cells has expanded tremendously. Globally, thousands of studies claiming to use stem cells in experimental therapies have now been in the investigation field. This may give the impression that such treatments have already been shown to be extremely effective in the context of healthcare. Despite some promising results, the vast majority of stem cell-based therapeutic applications are still in the experimental stage itself.6,25

The stem cells are a valuable resource for understanding organogenesis as well as the bodys continual regenerative capacity. These cells have brought up enormous anticipations among doctors, investigators, patients, and the public at large because of their ability to distinguish into a variety of cell types.25 These cells are necessary for living beings for a variety of reasons and can play a distinguishable role. Several stem cells can play all cell types roles, and when stimulated effectively, they can also repair damaged tissue. This capability has the potential to save lives as well as treat human injuries and tissue destruction. Moreover, different kinds of stem cells could be used for several purposes, including tissue formation, cell deficiency therapeutic interventions, and stem cell donation or retrieval.3,6,26

New research demonstrating that the successful application of stem cell treatments to patients has expressed hope that such regenerative strategies might very well one day is being used to address a wide variety of problematic ailments. Furthermore, clinical trials incorporating stem cell-based therapeutics have advanced at an alarming rate in recent years. Some of these studies had a significant impact on a wide range of medical conditions.10 As a regenerative medicine strategy, cell-based treatment is widely regarded as the most fascinating field of study in advanced science and medicine. Such technological innovation paves the way for an infinite number of transformational and potentially curable solutions to some of humanitys most pressing survival issues. Moreover, it is gradually becoming the next major concern in medical services.11

Modern data, which shows that the successful stem cell transplantation in beneficiaries has raised hopes on the certain rejuvenating approaches, will one day be used to treat many different types of challenging chronic conditions.24 Preliminary data from highly innovative investigations have documented that the prospective advancement of stem cells provides a wide range of life-threatening ailments that have so far eluded current medical therapy.2,10,11 Furthermore, clinical trials involving stem cell-based therapies have advanced at an unprecedented rate. Many of these studies had a significant impact on various disorders.19 Despite the increasing significance of articles concerning viable stem cell-based treatments, the vast majority of clinical experiments have still yet to receive full authorization for stem cell treatments confirmation.11,12,27

Even though the first case of AIDS were noted nearly 27 years ago, and the etiologic agent was noticed 25 years ago, still for the effective control of the AIDS pandemic continues to remain elusive.28 The HIV epidemic started in 1981 when a new virus syndrome defined by a weakened immune system was revealed in human populations across the globe. AIDS showed up to have a substantial reduction in CD4+ cell counts and also elevated B-cell multiplication.15,2831

The agent that causes AIDS, later named HIV, is a retroviral disease with a genomic structural system made up of 2 identical single-stranded RNA particles.3234 According to the Centres for Disease Control and Prevention, with over 1.1 million Americans are presently infected with the virus.31 Compromised immune processes in HIV and AIDS, as well as partial immune restoration, barriers are confirmed for HIV disease eradication. Innovative developmental strategies are essential to maximizing virus protection and enabling the host immune response to eliminate the virus.35

The progression of HIV infection in humans is divided into the following stages of acute infection, chronic infection, and AIDS.15,36 During the acute infection phase, the circulation has a high viral replication, is extremely infectious, that may or may not demonstrate flu-like clinical signs. In the chronic stage, the viral load is lesser than in the acute stage, and individuals are still infectious but may be symptomless. The patient has come to the end stage of AIDS whenever the CD4+ cell count begins to fall below 200 cells/mm or even when opportunistic infections are advanced.15,36

There are currently two types of HIV isolated HIV-1 and HIV-2.15,37,38 However, HIV-1 is the most common cause of AIDS throughout the world, while HIV-2 is only found in a few areas of an African country. Although both virions can cause AIDS, HIV-2 infection is much more likely to occur in central nervous system disorder.15 Besides this, HIV-2 seems to be less infectious than HIV-1, and HIV-2 infection induces AIDS to develop more slowly. Even though both HIV-1 and HIV-2 have a comparable genetic structure comprised of group-specific antigen, polymerase, and envelope genes, their genome organizational structures are differed.15,3739

HIV infiltrates immune cell types, CD4+ T cell types, and monocytes, resulting in a drop in T-cell counts below a critical level and the failure of cell-mediated immune function.15,40 The glycoprotein (gp120) observed in the virion envelope comes into contact with the CD4 particle with high affinity, allowing HIV to infect T cells. By interacting with their co-receptors, CXCR4 and CCR5, the virus infiltrates T cells and monocytes. The retrovirus uses reverse transcriptase to convert its RNA into DNA after attaching it to and entering the host cell. These newly replicated DNA copies then exit the host cell and infect other cells.15,40,41

HIV-1 is a retrovirus and belongs to a subset of retroviruses known as lentiviruses.38,42 Infection is the most common global health concern around the world.15 It has destroyed the millions of peoples health and continues to wreak havoc on the individual health of millions more. The pandemic of HIV-1 is the most devastating plague in the history of humans, as well as a significant challenge in the areas of medicine, public health, and biological science of research activities.34,43 Antiretroviral therapy is the only treatment that is commonly used. This is not a curative treatment; it must be used for the rest of ones life.15 Although antiretroviral therapy has reduced significantly HIV intensity and transmission, the virus has not been eradicated, and its continued presence can lead to additional health issues.44

Infection with the human immunodeficiency virus necessitates entry into target cells, such as through adhesion of the viral envelope to CD4 receptor sites.43 Cellular antiviral responses fail to eliminate the virus, resulting in a gradual depletion of CD4+ T cells and, finally, a severely compromised immune functioning system. Unfortunately, there is no cure for the virus that destroys immunity.4447 In advanced HIV infection, memory T-cell depletion primarily affects cellular and adaptive immune responses, with a minor impact on innate immune responses.48 Globally, 37.7 million people were living with HIV in 2020, and with 1.5 million individuals are infected with the virus.49 The advancement of stem cell therapy and the conduct of implemented clinical trials have revealed that stem cell treatment has high hopes for a range of medical conditions and implementations.15

Stem cell treatment has shown impressive outcomes in HIV management and has the potential to have significant implications for HIV treatment and prevention in the future. In HIV patients, stem cell therapy helps to suppress the viral load even while enabling antiretroviral regimens to be tapered. Interestingly, this practice led to a significant improvement in procedure outcomes soon after starting antiretroviral treatment.15 Stem cell transplantation can alleviate a wide variety of diseases that are currently incurable. They could also be used to create a novel anti-infection therapy strategic plan and to enhance the treatment of immunologic conditions such as HIV infection. HIV wreaks havoc on immune system cells.30,50

The virus infects and replicates within T-helper cells (T-cells), which are white immune system cells. T-cells are also referred to as CD4 cells. HIV weakens a persons immune system over time by pulverizing more CD4 cells and multiplying itself. More pertinently, if the individual has been unable to obtain anti-retroviral medicine, he will progressively fail to control the infectious disease and illnesses.3,15,42

Despite 36 years of scientific research, investigators are still trying to cure human HIV and its potential problem, AIDS.3,5153 HIV continues to face unconquerable dangers to human survival. This virus has developed the potential to avoid anti-retroviral therapy and tends to result in victim death.52 Investigators are still looking for effective and all-encompassing treatment for HIV and its complexity, AIDS.54 This massive amount of data revealed potential AIDS treatment targets.55 Thousands of research projects have yielded a great deal of information on the elusive AIDS life cycle to date.5456 These massive amounts of data supplied possible targets for AIDS treatment.33,55,56 In HIV-infected patients, using stem cell therapy can augment the process of keeping the viral load stagnant by permitting antiretroviral regimens to be tapered.15

Overall, stem cell-based strategies for HIV and AIDS treatment have recently emerged and have become a key area of research. Ideally, effective stem cell-based therapeutic approaches might have several benefits.30 Clinical studies encompassing stem cell therapy have shown substantial therapeutic effects in the treatment of various autoimmune, degenerative, and genetic problems.15,25 Substantial progress has been developed in the treatment of HIV infection using stem cell-based techniques.30

Successfully treated, clinical studies have shown that total tissue recovery is feasible.15,57 In the early 1980s, the first stem cell transplants were accomplished on HIV-positive patients who were unsure of their viral disease. Following the above preliminary aspects, many HIV-positive patients with concurrent malignant tumours or other hematologic disorders underwent allogeneic stem cell transplantation around the world.42 After ART became a common treatment option for patients,58,59 the procedures prognosis improved dramatically. In addition, a retrospective study of 111 HIV+ transplant patients demonstrated a mildly lower overall survivorship performance in comparison to an HIV-uninfected comparison group.60

Earlier, the primary problem for people living with HIV and AIDS was immunodeficiency caused by a loss of productive T-cells. Some clinicians intended to replenish lost lymphocytes through adoptive cell transplants in the initial days before efficacious antiretroviral therapy options were available. Immunologically, it is relatively simple in an isogeneic condition, as illustrated on HIV-positive individuals with just a correlating identical twin who received T-lymphocytes and stem cell transfusions to rebuild the weak immune status of the patient.60 Cell therapy transfusion may be used to remove resting virion genomes from CD4+ immune cells and macrophages mostly through genome-editing or cytotoxic anti-viral cells.15,60 Cell technology and stem cell biological reprogramming developments have made a significant contribution to novel strategies that may give confidence to HIV healing process.3 However, human embryonic stem cells can be distinguished into significant HIV target cells, according to several research findings.30,61,62

Initially, stem cell transplantation was believed to influence the clinical significance of HIV infection, but viral regulation was not accomplished in the discipline. Moreover, improvements in stem cell transplants utilizing synthetic or natural resistant cell resources, in combination with novel genetic manipulative tactics or the advancement of cytotoxic anti-HIV effector cells, have significantly accelerated this sector of HIV cell management.60 Multiple techniques are being introduced to overcome HIV, either through protecting cells from infectious disease or by continuing to increase immune responses to the viral infection.30 The various methods are as follows: Bone marrow stem cells Therapies, Autologous stem cell transplantations, Hematopoietic stem cell transplantation, Genetical modifications of Hematopoietic stem cells (HSCT), HSCT and HAART therapeutic approach, Human umbilical cord mesenchymal stem cell transplantation, Mesenchymal stem/stromal cells (MSCs) applications, CCR5 Delta32/Delta32 Stem-Cell Transplantation, CRISPR and stem cell applications, Induced Pluripotent Stem Cells applications.

According to the findings, circulating replicative HIV remains the most significant threat to effective AIDS therapy. As a result, a method for conferring resistance to circulating HIV particles is required. The effective viral burden in the human body would be significantly reduced if it were possible to defeat reproducing HIV particles.43,44 For the treatment of AIDS, a restorative approach that relies on bone marrow stem cells has been suggested.52 The proposed treatment method captures and eventually destroys circulating HIVs using receptor-integrated red blood cells. Red blood cell membranes can be equipped with the CD4 receptor and the C-C chemokine receptor type 5 and C-X-C chemokine receptor type 4 co-receptors, which will selectively bind circulating HIV particles.15,30,32,33,43,44,46,6365

The term autologous pertains to blood-forming stem cells obtained from the patient for use as a source of fresh blood cells followed by high-dose chemotherapeutic agents.66 Lymphoma is still the biggest cause of mortality in HIV patients. Autologous stem cell recovery or transplantation with high-dose treatments has long been supported as a treatment for certain types of cancer in HIV-negative patients, including leukaemia and lymphoma. Individuals over the age of 65, as well as those with health problems such as HIV, were excluded from initial transfusion experiments. Moreover, the treatment regimen mortality of transplantation has also been reduced significantly due to its use of peripheral blood stem cells rather than bone marrow and the use of newer marginal conditioning therapeutic strategies. HIV-infected clients may be able to utilize enough stem cells for an autologous transplant advancement in HIV management. High-dose Autologous stem cell transplant (ASCT) treatments are better than conventional treatment in people with relapsed non-Hodgkin lymphoma, according to randomized trial evidence. Similarly, studies on HIV-negative people with Hodgkin Lymphoma have shown that ASCT would provide patients with repetitive illness with long-term progression-free survival.66,67 Even so, the clinical trial on Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies report was explained as, the cell-associated HIV DNA and inducible infectious virus were not detectable in the blood of patients who attained complete chimerism.68

The study on long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates report findings was Genome editing in hematopoietic stem and progenitor cells (HSPCs) is a potential innovative approach for the treatment of numerous human disorders. This report shows that genome-edited HSPCs engraft and contribute to multilineage repopulation following autologous transplantation in a clinically relevant large animal model, which is an important step toward developing stem cell-based genome-editing therapeutics for HIV and possibly other illnesses.69

Research on comprehensive virologic and immune interpretation in an HIV-infected participant again just after allogeneic transfusion and analytical interruption of antiretroviral treatment findings are the instance of HIV-1 cure having followed allogeneic stem cell transplantation (allo-SCT), resulting allo-SCTs in HIV-1 positive participants have failed to cure the disease. It describes adjustments in the HIV reservoir in a single chronically HIV-infected client who had undergone allo-SCT for acute lymphoblastic leukaemia treatment and was obtaining suppressive antiretroviral treatment.

To estimate the size of the HIV-1 reservoir and describe viral phylogenetic and phenotypic modifications in immune cells, the investigators just used leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) from a 55-year-old man with chronic HIV infection prior and after allo-SCT. Once HIV-1 was found to be unrecognizable by numerous tests, including the PCR measurement techniques both of overall and fully integrated HIV-1 DNA, recompilation virus precise measurement by significant cell input quantifiable viral outgrowth assay, and in situ hybridization of intestine tissue, the client accepted to an analytic treatment interruption (ATI) with recurrent clinical observing on day 784 post-transplantation. He continued to remain aviremic off ART until ATI day 288, once a reduced virus rebound of 60 HIV-1 copies/mL resulted, which expanded to 1640 HIV-1 copies/mL five days later, urging ART reinitiation. Rebounding serum HIV-1 action sequences were phylogenetically distinguishable from pro-viral HIV-1 DNA discovered in circulating PBMCs before transplantation. It was indicated that allo-SCT tends to result in significant reductions in the magnitude of the HIV-1 reservoir and a >9-month ART-free cessation from HIV-1 multiplication.34

The Impact of HIV Infection on Transplant Outcomes after Autologous Peripheral Blood Stem Cell Transplantation: A Retrospective Study of Japanese Registry Data reported as ASCT is a successful treatment option for HIV-positive patients with non-Hodgkin lymphoma and multiple myeloma (MM). HIV infection was associated with an increased risk of overall mortality and relapse after ASCT for NHL in a study population.70

The procedure of delivering hematopoietic stem cells mostly through intravenous infusion to restore normal haematopoiesis or treat cancer is known as hematopoietic stem cell transplantation.71 There has recently been a rise in the desire to develop strategies for treating HIV/AIDS diseases employing human hematopoietic stem cells,30 along with this Hutter and Zaia were evaluated the background of Haematopoietic stem cell transplantation (HSCT) in HIV-infected individuals.42

Attempts to use HSCT as a technique for immunologic restoration in AIDS patients or as a therapeutic intervention for malignant tumours were initially insufficient. Regretfully, in the absence of sufficient ART, HSCT seemed to have no impact on the evolution of HIV infection, and the majority of the patients ended up dead of rapidly deteriorating immunosuppression or reoccurring lymphoma or leukaemia. A specific instance report described how an un-associated, matched donor supplied allogeneic HSCT to a patient with refractory lymphoma. The virus was unrecognizable by isolating or PCR of peripheral blood mononuclear cells commencing on day 32 after transplantation. Although HIV-1 was unrecognizable by cultural environment or PCR of several tissues examined at mortem, the patient died of recurring lymphoma on day 47. Another client who obtained both allogeneic HSCT and zidovudine had similar results, with HIV-1 becoming unnoticeable in the blood by PCR analysis. In some other particular instances, a 25-year-old woman with AIDS who obtained an allogeneic HSCT from a corresponding, unfamiliar donor after controlling with busulfan and cyclophosphamide and ART with zidovudine and IFN-2 regimen continued to live for 10 months before falling victim to adult respiratory distress. However, PCR testing of autopsy tissues revealed that they were HIV-1 negative.72

Recent research discovered significant progress towards the clinical application of stem cell-based HIV therapeutic interventions, principally illustrating the opportunity to effectively undertake a large-scale phase two HSC-based gene therapy experiment. In this investigation, the research team used autologous adult HSCs that had been transduced to a retroviral vector that usually contains a tat-vpr-specific anti-HIV ribozyme to develop cells that were less vulnerable to productive infection,73 whereas vector-containing cells have been discovered for extended periods (more than 100 weeks in most people) and CD4+ T cell gets counted were significantly high within anti-HIV ribozyme treating people group compared with the placebo group, the impacts on viral loads were minimal. The studys success, even so, is based on the realization that a stem cell-based strategy like this is being used as a more conventional and efficacious therapeutic approach.30 Some other latest clinical studies used a multi-pronged RNA-based strategic plan which included a CCR5-targeted ribozyme, an shRNA targeting tat/rev transcripts, and a TAR segment decoy.74

These crucial research findings are explained on lentiviral-based gene therapy vectors that can genetically manipulate both dividing and non-dividing HSCs and are less likely to cause cellular changes than murine retro-viral-based vectors. Long-term engraftment and multipotential haematopoiesis have been demonstrated in vector-containing and expressing cells, according to the researchers. Whereas the antiviral effectiveness was not reviewed, the results demonstrate the strategys protection, which helps to expand well for the possibility of a lentiviral-based approach in the upcoming years.30

A further approach, with a different emphasis, has been started up in the hopes of trying to direct immune function to target specific HIV to overcome barriers to attempting to clear the virus from the patient's body. These strategies use gene treatment innovations on peripheral blood cells to biologically modify cells so that they assert a receptor or chimeric particle that enables them to especially target a specific viral antigen,75 deception of HIV-infected peoples peripheral blood T cells raises issues to be addressed, such as the effects of ongoing HIV infection and ex vivo modification on the capabilities and lifetime of peripheral blood cells. Further to that, the above genetically manipulated cells would demonstrate their endogenous T cell receptors, and the representation of the newly introduced receptor could outcome in cross-receptor pairing, resulting in self-reactive T cells. Most of these deficiencies could be countered by enabling specific developmental strategies to take place that can start generating huge numbers of HIV-specific cells in a renewable, consistent way that can restore defective natural immune activity against HIV.30

One strategy being recognized is the application of B cells obtained from HSCs to demonstrate anti-HIV neutralizing specific antibodies. While animal studies have shown that neutralizing antibodies could protect against infection, and extensively neutralizing antibodies have been noticed in some HIV-infected persons, safety from a single engineered antibody might be exceptional.76,77 Realizing antibody binding and virus neutralization may assist in the development of chimeric receptors or single-chain therapeutic antibodies with recognition domains for other techniques that identify cellular immunity against HIV-infected cells.78,79 Thereby, genetically modifying HSCs to generate B cells that produce neutralizing anti-HIV specific antibodies, or engineering HSCs to enable multipotential haematopoiesis of cells that express a chimeric cellular receptor usually contains an antibody recognition domain, indicate one arm of an HSC-based engineered immunity process.30

A further technique of using HSCs that were genetically altered with molecularly cloned T-cell receptors or chimeric molecules particular to HIV to yield antigen-specific T cells. The basic difference in this strategy is that the cells produced from HSCs after standard advancement in the bone marrow and thymus are made subject to normal central tolerance modalities and are antigen-specific naive cells, and therefore do not have the ex-vivo manipulation and impaired functioning or exhaustion problems that other external cell modification methods would have. In this context, the latest actual evidence research using a molecularly cloned T cell receptor particular to an HIV-1 Gag epitope in the aspect of HLA-A*0201 revealed that HSC altered in this ability can progress into fully functioning, mature HIV specialized CD8+ T cells in human thymic tissue that conveys the acceptable constrained HLA-A*0201 particles.80 This explores the possibility of genetically engineering HSCs with a molecularly cloned receptor and signifies a step toward a better understanding and application of initiated T cell responses, which would probably result in the eradication of HIV infection from the body, similar to the natural immune function of other virus infections and pathogenic organisms.30

In an allogeneic transplantation, donor stem cells replace the patients cells.66 Allogeneic hematopoietic stem cell transplantation (HSCT) has appeared as one of the most potent treatment possibilities for many people who suffer from hemopoietic system carcinomas and non-malignant ailments.81 Both HIV-cured people have received HSCT utilizing CCR5 132 donor cells.82,83 This implies that HIV eradication necessitates a decrease in the viral reservoir through the myeloablative procedures,8486 Having followed that, immune rebuilding with HIV-resistant cells was carried out to prevent re-infection.45 The possibility of adoptive transfer of ex vivo-grown, virus-specific T-cells to prevent and control infectious diseases (eg, Cytomegalovirus and EBV) in immunocompromised patients helps to make adoptive T-cell treatment a feasible strategy to inhibit HIV rebound having followed HSCT.81,87,88

The Engineered Zinc Finger Protein Targeting 2LTR Inhibits HIV Integration in Hematopoietic Stem and Progenitor Cell-Derived Macrophages: In Vitro Study, the researchers investigated the efficacy and safety of 2LTRZFP in human CD34+ HSPCs. Researchers used a lentiviral vector to transduce 2LTRZFP with the mCherry tag (2LTRZFPmCherry) into human CD34+ HSPCs. The study findings suggest that the anti-HIV-1 integrase scaffold is an enticing antiviral molecule that could be utilised in human CD34+ HSPC-based gene therapy for AIDS patients.89

The fundamental element of HIV management is stem cell genetic modification, which involves genetically enhanced patient-derived stem cells to overcome HIV infection. In this sector, numerous experimental studies, in vitro as well as in vivo examinations, and positive outcomes for AIDS patients have been conducted.65,74 Genetic engineering for HIV-infected individuals can provide a once-only intervention that minimizes viral load, restores the immune system, and minimizes the accumulated toxicities concerned with highly active antiretroviral therapy (HAART).73 HSCs can be genetically altered, permitting for the addition of exogenous components to the progeny that protects them from direct infectious disease and/or enables them to target a specific antigen. Besides that, HSC-based strategies can enhance multilineage hemopoietic advancement by re-establishing several arms of the immune function. Eventually, as HSCs can be produced autologously, immunologic tolerance is typically high, enabling effective engraftment and subsequent distinction into the fully functioning mature hematopoietic cells.30

The utilization of human HSCs to rebuild the immune function in HIV disease is one application that tries to preserve newly formed cells from HIV infection, while another attempts to develop immune cells that attack HIV infected cells. While each initiative has many different aspects at the moment, they represent huge attention to HIV/AIDS therapies that, most likely when integrated with the other therapeutic approaches, would result in the body trying to overcome the obstacles needed for the virus to be effectively cleaned up.30

While HSC transplantation technique and processes are not accurately novel, as they are commonly and effectively used to address a wide variety of haematological diseases and malignant neoplasms,90 trying to combine them with a gene therapeutic strategy represents a unique and possibly potent therapeutic approach for HIV and AIDS-related ailments. As the results of HIV-infected patients who obtained autologous HSCT continued to improve, there was growing interest in genetically altered stem cells that were tolerant to HIV disease. Multiple logistical challenges have impeded the advancement of genetically modified hematopoietic stem cells as a conceivable therapeutic option for HIV/AIDS.72,73

UCLAs Eli and Edythe Broad Center for Restorative Medicine and Stem Cell Studies is one bit closer to constructing an instrument to arm the bodys immune system to attack and defeat HIV. Dr. Kitchen et al are the first ones to disclose the use of a chimeric antigen receptor (CAR), a genetically manipulated molecule, in blood-forming stem cells. In the experiment, the research team introduced a CAR gene into blood-forming stem cells, which were then moved into HIV-infected mice that had been genetically programmed. The scientists found that CAR-carrying blood stem cells efficiently transformed into fully functioning T cells that have the ability to kill HIV-infected cells in mice. The outcome was an 80-to-95 percentage reduction in HIV levels, suggesting that stem-cell-based genetic engineering with a CAR might be a viable and effective approach for treating HIV infection among humans. The CAR initiative, according to Dr. Kitchen, is much more able to adapt and ultimately more efficient, which can conceivably be used by others. If any further experiment showcases keep promising, the scientists expect that a practice based on their strategy will be accessible for clinical development within the next 510 years.91

HSCT and HAART therapeutic approaches in treating HIV/AIDS as the emergence of highly active antiretroviral therapy (HAART) in the 1990s improved survival rates of HIV infection, leading to a major dramatic drop in the occurrence of AIDS and AIDS-related mortalities. As an outcome, there is much less involvement with using HSCT as a therapy for HIV infection.28,33,43,67,86

A randomized clinical trial of human umbilical cord mesenchymal stem cell transplant among HIV/AIDS immunological non responders investigation, the researchers examined the clinical efficacy of transfusion of human umbilical cord mesenchymal stem cells (hUC-MSC) for immunological non-responder clients with long-term HIV disease who have an unmet medical need in the aspect of effective antiretroviral therapy. From May 2013 to March 2016, 72 HIV-infected participants were admitted in this stage of the randomized, double-blind, multi-center, placebo-controlled dose-determination investigation. They were either given a high dose of hUC-MSC of 1.5106/kg body weight as well as small doses of hUC-MSC of 0.5106/kg body weight, or a placebo application. During the 96-week follow-up experiment, interventional and immunological character traits were analysed. They found that hUC-MSC therapy was both safe and efficacious among humans. There was a significant rise in CD4+ T counts after 48 weeks of treatment in both the high-dose (P 0.001) and low-dose (P 0.001) groups, but no changes in the comparison group.92

One interesting invention made by a team of UC Davis investigators is the recognition of a particular form of stem cell that can minimize the quantity of the virus that tends to cause AIDS, thus dramatically increasing the bodys antiviral immune activity. Mesenchymal stem/stromal cells (MSCs) furnish an incredible opportunity for a creative and innovative, multi-pronged HIV cure strategic plan by augmenting prevailing HIV potential treatments. Even while no antivirals have been used, MSCs have been able to increase the hosts antiviral responses. MSC therapeutic approaches require specialized delivery systems and good cell quality regulation. The studys findings lay the proper scientific foundation for future research into MSC in the ongoing treatment of HIV and other contagious diseases in the clinical organization.35

Infection with HIV-1 necessitates the existence of both specific receptors and a chemokine receptor, particularly chemokine receptor 5 (CCR5).46 Resistance to HIV-1 infection is attained by homozygozygozity for a 32-bp removal in the CCR5 allele.93 In this investigation, stem cells were transplanted in a patient with severe myeloid leukaemia and HIV-1 infection from a donor who was homozygous to Chemokine receptor 5 delta 32. The client seemed to have no viral relapses after 20 months of transplantation and attempting to stop antiretroviral medicine. This finding highlights the essential role that CCR5 tries to play in HIV-1 infection maintenance.86

In comparison, additional HIV-1-infected people who have received allogeneic stem cell transplants with cells from CCR5 truly wild donors did not have long-term relapses from HIV-1 rebound, with 2 of these patients trying to report viral reoccurrence 12 as well as 32 weeks after analytic treatment interruption, respectively. Among these 2 patients, allogeneic stem cell transplantation probably reduced but did not eliminate latently HIV-infected cells, enabling persistent viral reservoirs to activate viral rebound. This viewpoint may not rule out the potential that allogeneic hematopoietic stem cell transplantation might result in a much more comprehensive or near-complete elimination of viral reservoirs, enabling long-term drug-free relapse of HIV-1 infection in some contexts.84 As just one report demonstrated a decade earlier, a curative treatment for HIV-1 remained elusive. The Berlin Patient has undergone 2 allogeneic hematopoietic stem cell transplantations to cure his acute myeloid leukaemia utilizing a potential donor with a homozygous genetic mutation in HIV coreceptor CCR5 (CCR532/32).15,34,46,64,65,72,82,84,86,9496 Other similar studies with CCR5 receptor targets are as follows: Automated production of CCR5-negative CD4+-T cells in a GMP compatible, clinical scale for treatment of HIV-positive patients,97 Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations,98 Conditional suicidal gene with CCR5 knockout.99

Clustered regularly interspaced short palindromic repeats CRISPR/Cas9 is a promising gene editing approach that can edit genes for gain-of-function or loss-of-function mutations in order to address genetic abnormalities. Despite the fact that other gene editing techniques exist, CRISPR/Cas9 is the most reliable and efficient proven method for gene rectification.100103

Genome engineering employing CRISPR/Cas has proven to be a strong method for quickly and accurately changing specific genomic sequences. The rise of innovative haematopoiesis research tools to examine the complexity of hematopoietic stem cell (HSC) biology has been fuelled by considerable advancements in CRISPR technology over the last five years. High-throughput CRISPR screenings using many new flavours of Cas and sequential and/or functional outcomes, in specific, have become more effective and practical.104,105

The power of the CRISPR/Cas system is that it can specifically and efficiently target sequences in the genome with just a single synthetic guide RNA (sgRNA) and a single protein. Cas9 is directed to the specific DNA sequence by the sgRNA, which causes double stranded breaks and activates the cells DNA repair processes. Non-homologous end joining can cause insertiondeletion (indel) substitutions at the target location, whereas homology-directed repair can use a template DNA to insert new genetic material.104,106

The possibility for CRISPR/Cas9 to be used in the hematopoietic system was emphasised as pretty shortly after it was initiated as a new genome editing method.106,107 The efficiency with which CRISPR-mediated alteration can be used to evaluate hematopoietic stem/progenitor and mature cell function via transplantation. As a result, hematopoietic research has significantly advanced with the implementation of these technologies. Whilst single-gene CRISPR/Cas9 programming is a significant tool for testing gene function in primary hematopoietic cells, high-throughput screenings potentially offer CRISPR/Cas9 an even greater advantage in hematopoietic research.104

While understanding human haematological disorders requires the ability to mimic diseases, the ultimate goal is to transfer this innovation into therapies. Despite significant advancements in CRISPR technology, there are still barriers to overcome before CRISPR/Cas9 can be used effectively and safely in humans. CRISPR has also been used to target CCR5 in CD34+ HSPCs in an effort to make immune cells resistant to HIV infection, as CCR5 is an important coreceptor for HIV infection.104

CRISPR is a modern genome editing technique that could be used to treat immunological illnesses including HIV. The utilization of CRISPR in stem cells for HIV-related investigation, on the other end, was ineffective, and much of the experiment was done in vivo. The new research idea is about increasing CRISPR-editing efficiencies in stem cell transplantation for HIV treatment, as well as its future perspective. The possible genes that enhance HIV resistance and stem cell engraftment should be explored more in the future studies. To strengthen HIV therapy or resistance, double knockout and knock-in approaches must be used to build a positive engraftment. In the future, CRISPR/SaCas9 and Ribonucleoprotein (RNP) administration should be explored in the further investigations.108 As well as some different title studies were explained the effectiveness of the CRISPR gene editing technology on the management of HIV/AIDS including: CRISPR view of hematopoietic stem cells: Moving innovative bioengineering into the clinic,104 CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukaemia,109 Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice,110 Extinction of all infectious HIV in cell culture by the CRISPR-Cas12a system with only a single crRNA,111 HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells,112 CRISPR-Cas9 Mediated Exonic Disruption for HIV-1 Elimination,113 RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection,114 CRISPR/Cas9 Ablation of Integrated HIV-1 Accumulates Pro viral DNA Circles with Reformed Long Terminal Repeats,115 CRISPR-Cas9-mediated gene disruption of HIV-1 co-receptors confers broad resistance to infection in human T cells and humanized mice,116 Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9,117 Transient CRISPR-Cas Treatment Can Prevent Reactivation of HIV-1 Replication in a Latently Infected T-Cell Line,118 CCR5 Gene Disruption via Lentiviral Vectors Expressing Cas9 and Single Guided RNA Renders Cells Resistant to HIV-1 Infection,119 CRISPR/Cas9-Mediated CCR5 Ablation in Human Hematopoietic Stem/Progenitor Cells Confers HIV-1 Resistance In Vivo.109

Induced pluripotent stem cells (iPSCs) have significantly advanced the field of regenerative medicine by allowing the generation of patient-specific pluripotent stem cells from adult individuals. The progress of iPSCs for HIV treatment has the potential to generate a continuous supply of therapeutic cells for transplantation into HIV-infected patients. The title of the study is reported on Generation of HIV-1 Resistant and Functional Macrophages from Hematopoietic Stem Cellderived Induced Pluripotent Stem Cells. In this investigation, researchers used human hematopoietic stem cells (HSCs) to produce anti-HIV gene expressing iPSCs for HIV gene therapy. HSCs were dedifferentiated into constantly growing iPSC lines using 4 reprogramming factors and a combination anti-HIV lentiviral vector comprising a CCR5 shRNA and a human/rhesus chimeric TRIM5 gene. After directing the anti-HIV iPSCs toward the hematopoietic lineage, a large number of colony-forming CD133+ HSCs were acquired. These cells were distinguished further into functional end-stage macrophages with a normal phenotypic profile. Upon viral challenge, the anti-HIV iPSC-derived macrophages displayed good protection against HIV-1 infection. Researchers have clearly shown how iPSCs can establish into HIV-1 resistant immune cells and explain their prospective use in HIV gene and cellular therapies.120

Some other similar titles of the studies reported on the effectiveness of IPSCs on HIV/AIDS managements are as follows: Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA,121 Generation of HIV-1-infected patients gene-edited induced pluripotent stem cells using feeder-free culture conditions,122 A High-Throughput Method as a Diagnostic Tool for HIV Detection in Patient-Specific Induced Pluripotent Stem Cells Generated by Different Reprogramming Methods,123 Genetically edited CD34+ cells derived from human iPS cells in vivo but not in vitro engraft and differentiate into HIV-resistant cells,124 Engineered induced-pluripotent stem cell-derived monocyte extracellular vesicles alter inflammation in HIV humanized mice,125 Sustainable Antiviral Efficacy of Rejuvenated HIV-Specific Cytotoxic T Lymphocytes Generated from Induced Pluripotent Stem Cells.126

Recently, one HIV patient appeared to be virus-free after having undergone a stem-cell transfusion in which their WBCs were changed with HIV-resistant variations.84 Timothy Ray Brown also noted as the Berlin patient, who is still virus-free, was the first individual to undertake stem-cell transplantation a decade earlier. The most recent patient, like Brown, had a type of leukaemia that was vulnerable to chemo treatments. They required a bone marrow transplantation, which involved removing their blood cells and replacing them with stem cells from a donor cell.5,31,34,41,127130 Rather than simply choosing a suitable donor, Ravindra Gupta et al chose one who already had 2 copies of a mutant within the CCR5 gene,128,131 which provides resistance to HIV infection.3

Additionally, this gene encodes for a specific receptor of white blood cells that are assisted in the bodys immunological responses. The transplant, according to Guptas team, completely replaced the clients White cells with HIV-resistant forms.41,83 Cells in the patients blood disrupted expressing the CCR5 receptor, making it unfeasible for the clients form of HIV to infect the above cells again. The scientists determined that the virus had been cleared from the patients blood after the transplantation. Besides that, after 16 months, the client has withdrawn antiretroviral treatment. The infection was not detected in the most recent follow-up, which occurred 18 months after the treatment was discontinued. Adam, also known as the London patient, was the second person to be cured of HIV as a result of a stem cell transfusion. This discovery is an important step forward in HIV research because it may aid in the detection of potential future therapeutic interventions. It must be noted, but even so, that this is not an extensively used HIV treatment. For HIV-infected patients, antiretroviral drugs have been the foremost therapeutic option.3,31,41,94,129,130 It also encourages many investigators and clinicians to look at the use of stem cells in the treatment of a wide range of serious medical conditions. The reprogramming abilities of stem cells, as well as their accessibility, have created a window of opportunity in medical research. The clinical utility of stem cells is forecast to expand rapidly in the coming years.

On Feb 15, 2022, scientific researchers confirmed that a woman had become the 3rd person in history to be successfully treated for HIV, the virus that causes AIDS, after just receiving a stem-cell transfusion that has used cells from cord blood. Within those transplant recipients, adult hematopoietic stem cells have been used; these are stem cells that eventually develop into all blood cell types, which include white blood cells, these are a vital component of the immune framework. Even so, the woman who had fairly recently been completely cured of HIV infection had a more unique experience than that of the 2 men who were actually cured before her.132

The clients physician, Dr. JingMei Hsu of Weill Cornell Medicine in New York, informed them that, she had been discharged from the hospital just 17 days after her procedure was performed, even with no indications of graft vs host ailment. The woman was HIV-positive but also had acute myeloid leukaemia, a blood cancer of the bone marrow that affects blood-forming cells. She had likely received cord blood as a successful treatment for both her cancer and HIV once her doctors decided on a potential donor well with HIV-blocking gene mutation. Cord blood comprises a high accumulation of hematopoietic stem cells; the blood is obtained during a childs birth and donated by the parents.132

The patients donor was partly nearly matched, and she received stem cells from a close family member to enhance her immune function after the transfusion. The procedure was performed on the woman in August of 2017. She chose to discontinue taking antiretroviral drugs, the standardized HIV intervention, 37 months upon her transfusion. After more than 14 months, there is no evidence of the viral infection or antibodies against it in her blood. Umbilical cord blood, in reality, is much more commonly accessible and simpler to try to match to beneficiaries than bone marrow. Perhaps, some research suggests that the method could be more available to HIV patients than bone marrow transplantation. Nearly 38 million people worldwide are infected with HIV. The potential for using partly matched umbilical cord blood transplantation increases the chances of choosing appropriate suitable donors for these clients considerably.132

It is really exciting to see the earlier terminally ill diseases of being effectively treated. In recent times, there has been a surge of focus on stem cell research.3 Stem cell therapy advancements in inpatient care are receiving a growing amount of attention.20 HIV/AIDS has been and remains a significant health concern around the world. Effective control of the HIV pandemic will necessitate a thorough understanding of the viruss transmission.32

Despite concerns about full compliance and adverse reactions, HAART has demonstrated to be able to succeed and is a sign specifically targeted form of treatment against HIV advancement. As illustrated by the first case of HIV infection relapse attained by bone marrow transplant, anti-HIV HPSC-based stem cell treatment and genotype technology have established a possible future upcoming technique to try to combat HIV/AIDS.

Investigators have conducted experiments with engineering distinct anti-HIV genetic traits trying to target different phases of HIV infection utilizing advanced scientific modalities. In numerous in vivo and in vitro animal studies, HSPCs and successive mature cells were secured from HIV infection by trying to target genetic factors in the infection. Anti-HIV gene engineering of HSPCs is safe and efficacious.15

The number of stem-cell-based research trials has risen in recent years. Thousands of studies claiming to use stem cells in experimental therapies have been registered worldwide. Despite some promising results, the majority of clinical stem cell technologies are still in their early life. These achievements have drawn attention to the possibility of the potential and advancement of various promising stem cell treatments currently in development.11

HIV remains a major danger to humanity. This virus has developed the ability to evade antiretroviral medication, resulting in the death of individuals. Scientists are constantly looking for a treatment for HIV/AIDS that is both effective and efficient.52 The 1st treatments in HIV+ clients were conducted in the early 1980s, even though they were cognizant of their viral disease. Following these early cases, allogeneic SCT was used to treat HIV+ patients with associated cancer or other haematological disorders all over the world. Stem cell transplantation developments have also stimulated the improvement of innovative HIV therapeutic approaches, especially for large goals like eradication and relapse.60

Numerous stem cell therapy progressions have been recognized with autologous and allogeneic hematopoietic stem cell transplantation, as well as umbilical cord blood mesenchymal stem cell transplant in AIDS immunologic non-responders. Whereas this sector continues to advance and distinguishing directives for these cells become much more effective, totipotent stem cells such as hESC and the recently reported induced pluripotent stem cells (iPSC) could be very useful for genetic engineering methods to counter hematopoietic abnormalities such as HIV disease.133135

Immunocompromised people are at a higher risk of catching life-threatening diseases. The perseverance of latently infected cells, which is formed by viral genome inclusion into host cell chromosomes, is a significant challenge in HIV-1 elimination. Stem cell therapy is producing impressive patient outcomes, illustrating not only the broad relevance of these strategies but also the huge potential of cell and gene treatment using adult stem cells and somatic derivative products of pluripotent stem cells (PSCs).

Stem cells have enormous regeneration capacity, and a plethora of interesting therapeutic uses are on the frontier. This is a highly interdisciplinary scientific field. Evolutionary biologists, biological technicians, mechanical engineers, and others that have evolved novel concepts and decided to bring them to medical applications are required to make important contributions. Further to that, recent advancements in several different research areas may contribute to stem cell application forms that are novel. Several hurdles must be conquered, however, in the advancement of stem cells. On the other hand, this discipline appears to be a promising and rapidly expanding research area.

Stem cell-based approaches to HIV treatment resemble an innovative approach to trying to rebuild the ravaged bodys immune system with the utmost goal of eliminating the virus from the body. We will probably see effective experiments from the next new generation of stem cell-based strategies shortly, which will start serving as a base for the further development and use of these techniques in a range of treatment application areas for other chronic diseases.

My immense pleasure was mentioned to family members and friends, who supported and encouraged me in every activity.

There was no funding for this work.

The authors declare that they have no conflicts of interest in relation to this work.

1. Zakrzewski W, Dobrzyski M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10:68. doi:10.1186/s13287-019-1165-5

2. Nadig RR. Stem cell therapy hype or hope? A review. J Conserv Dent JCD. 2009;12:131138. doi:10.4103/0972-0707.58329

3. Tasnim KN, Adrita SH, Hossain S, Akash SZ, Sharker S. The prospect of stem cells for HIV and cancer treatment: a review. Pharm Biomed Res. 2020;6:1726.

4. Weissman IL. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science. 2000;287:14421446. doi:10.1126/science.287.5457.1442

5. Pernet O, Yadav SS, An DS. Stem cellbased therapies for HIV/AIDS. Adv Drug Deliv Rev. 2016;103:187201. doi:10.1016/j.addr.2016.04.027

6. Kolios G, Moodley Y. Introduction to stem cells and regenerative medicine. Respir Int Rev Thorac Dis. 2013;85:310.

7. Ebrahimi A, Ahmadi H, Ghasrodashti ZP, et al. Therapeutic effects of stem cells in different body systems, a novel method that is yet to gain trust: a comprehensive review. Bosn J Basic Med Sci. 2021;21:672701. doi:10.17305/bjbms.2021.5508

8. Introduction stem cells. Available from: https://www.dpz.eu/en/platforms/degenerative-diseases/research/introduction-stem-cells.html. Accessed December 19, 2021.

9. Hu J, Chen X, Fu S. Stem cell therapy for thalassemia: present and future. Chin J Tissue Eng Res. 2018;22:3431.

10. Aly RM. Current state of stem cell-based therapies: an overview. Stem Cell Investig. 2020;7:8. doi:10.21037/sci-2020-001

11. Chari S, Nguyen A, Saxe J. Stem cells in the clinic. Cell Stem Cell. 2018;22:781782. doi:10.1016/j.stem.2018.05.017

12. De Luca M, Aiuti A, Cossu G, Parmar M, Pellegrini G, Robey PG. Advances in stem cell research and therapeutic development. Nat Cell Biol. 2019;21:801811. doi:10.1038/s41556-019-0344-z

13. Hipp J, Atala A. Sources of stem cells for regenerative medicine. Stem Cell Rev. 2008;4:311. doi:10.1007/s12015-008-9010-8

14. Bobba S, Di Girolamo N, Munsie M, et al. The current state of stem cell therapy for ocular disease. Exp Eye Res. 2018;177:6575. doi:10.1016/j.exer.2018.07.019

15. Khalid K, Padda J, Fernando RW, et al. Stem cell therapy and its significance in HIV infection. Cureus. 2021;13. doi: 10.1038/d41586-019-00798-3

16. Gq D, Morrell CN, Tarango C. Stem cells: roadmap to the clinic. J Clin Invest. 2010;121:120. doi:10.1172/JCI39828

17. Prentice DA. Adult Stem Cells. Circ Res. 2019;124:837839. doi:10.1161/CIRCRESAHA.118.313664

18. McKee C, Chaudhry GR. Advances and challenges in stem cell culture. Colloids Surf B Biointerfaces. 2017;159:6277. doi:10.1016/j.colsurfb.2017.07.051

19. Prez Lpez S, Otero Hernndez J. Advances in stem cell therapy. In: Lpez-Larrea C, Lpez-Vzquez A, Surez-lvarez B, editors. Stem Cell Transplantation. New York, NY: Springer US; 2012:290313.

20. Zhang F-Q, Jiang J-L, Zhang J-T, Niu H, X-Q F, Zeng -L-L. Current status and future prospects of stem cell therapy in Alzheimers disease. Neural Regen Res. 2020;15:242250. doi:10.4103/1673-5374.265544

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PROMISING STEM CELL THERAPY IN THE MANAGEMENT OF HIV & AIDS | BTT - Dove Medical Press

IPS Cell Therapy Comments Off on PROMISING STEM CELL THERAPY IN THE MANAGEMENT OF HIV & AIDS | BTT – Dove Medical Press | July 8th, 2022

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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Gene & Cell Therapy FAQs | ASGCT - American Society of Gene & Cell ...

IPS Cell Therapy Comments Off on Gene & Cell Therapy FAQs | ASGCT – American Society of Gene & Cell … | June 30th, 2022

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

IPS Cell Therapy Comments Off on The benefits and risks of stem cell technology – PMC | June 30th, 2022