Stem cells as delivery vehicles for regenerative medicinechallenges and perspectives

The use of stem cells as carriers for therapeutic agents is an appealing modality for targeting tissues or organs of interest. Combined delivery of cells together with various information molecules as therapeutic agents has the potential to enhance, modulate or even initiate local or systemic repair processes, increasing stem cell efficiency for regenerative medicine applications. Stem-cell-mediated delivery of genes, proteins or small molecules takes advantage of the innate capability of stem cells to migrate and home to injury sites. As the native migratory properties are affected by in vitro expansion, the existent methods for enhancing stem cell targeting capabilities(modified culture methods, genetic modification, cell surface engineering) are described. The role of various nanoparticles in eq-uipping stem cells with therapeutic small molecules is revised together with their class-specific advantages and shortcomings. Modalities to circumvent common challenges when designing a stem-cell-mediated targeted delivery system are described as well as future prospects in using this approach for regenerative medicine applications.

WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells “Ins” and “Outs” of mesenchymal stem cell osteogenesis in regenerative medicine

Repair and regeneration of bone requires mesenchymal stem cells that by self-renewal,are able to generate a critical mass of cells with the ability to differentiate into osteoblasts that can produce bone protein matrix(osteoid)and enable its mineralization.The number of human mesenchymal stem cells(hMSCs)diminishes with age and ex vivo replication of hMSCs has limited potential.While propagating hMSCs under hypoxic conditions may maintain their ability to self-renew,the strategy of using human telomerase reverse transcriptase(hTERT)to allow for hMSCs to prolong their replicative lifespan is an attractive means of ensuring a critical mass of cells with the potential to differentiate into various mesodermal structural tissues including bone.However,this strategy must be tempered by the oncogenic potential of TERT-transformed cells,or their ability to enhance already established cancers,the unknown differentiating potential of high population doubling hMSCs and the source of hMSCs(e.g.,bone marrow,adipose-derived,muscle-derived,umbilical cord blood,etc.)that may provide peculiarities to self-renewal,differentiation,and physiologic function that may differ from non-transformed native cells.Tissue engineering approaches to use hMSCs to repair bone defects utilize the growth of hMSCs on three-dimensional scaffolds that can either be a base on which hMSCs can attach and grow or as a means of sequestering growth factors to assist in the chemoattraction and differentiation of native hMSCs.The use of whole native extracellular matrix(ECM)produced by hMSCs,rather than individual ECM components,appear to be advantageous in not only being utilized as a three-dimensional attachment base but also in appropriate orientation of cells and their differentiation through the growth factors that native ECM harbor or in simulating growth factor motifs.The origin of native ECM,whether from hMSCs from young or old individuals is a critical factor in"rejuvenating"hMSCs from older individuals grown on ECM from younger individuals.

Stem cells, a two-edged sword: Risks and potentials of regenerative medicine

The recent advancements in stem cell (SC) biology have led to the concept of regenerative medicine, which is based on the potential of SC for therapies aimed to facilitate the repair of degenerating or injured tissues. Nonetheless, prior to large scale clinical appli- cations, critical aspects need to be further addressed, including the long-term safety, tolerability, and efficacy of SC-based treatments. Most problematic among the risks of SC-based therapies, in addition to the pos- sible rejection or loss of function of the infused cells, is their potential neoplastic transformation. Indeed, SCs may be used to cure devastating diseases, but their specific properties of self-renewal and clonogenicity may render them prone to generate cancers. In this respect, ‘Stemness’ might be seen as a two-edged sword, its bright side being represented by normal SCs, its dark side by cancer SCs. A better understand- ing of SC biology will help fulfill the promise of regen- erative medicine aimed at curing human pathologies and fighting cancer from its roots.

Adipose stromal/stem cells in regenerative medicine:Potentials and limitations

This article presents the stem and progenitor cells from subcutaneous adipose tissue,briefly comparing them with their bone marrow counterparts,and discussing their potential for use in regenerative medicine.Subcutaneous adipose tissue differs from other mesenchymal stromal/stem cells(MSCs)sources in that it contains a pre-adipocyte population that dwells in the adventitia of robust blood vessels.Pre-adipocytes are present both in the stromal-vascular fraction(SVF;freshly isolated cells)and in the adherent fraction of adipose stromal/stem cells(ASCs;in vitro expanded cells),and have an active role on the chronic inflammation environment established in obesity,likely due their monocyticmacrophage lineage identity.The SVF and ASCs have been explored in cell therapy protocols with relative success,given their paracrine and immunomodulatory effects.Importantly,the widely explored multipotentiality of ASCs has direct application in bone,cartilage and adipose tissue engineering.The aim of this editorial is to reinforce the peculiarities of the stem and progenitor cells from subcutaneous adipose tissue,revealing the spheroids as a recently described biotechnological tool for cell therapy and tissue engineering.Innovative cell culture techniques,in particular 3D scaffold-free cultures such as spheroids,are now available to increase the potential for regeneration and differentiation of mesenchymal lineages.Spheroids are being explored not only as a model for cell differentiation,but also as powerful 3D cell culture tools to maintain the stemness and expand the regenerative and differentiation capacities of mesenchymal cell lineages.

Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine

Mesenchymal stem cells(MSCs)represent the most clinically used stem cells in regenerative medicine.However,due to the disadvantages with primary MSCs,such as limited cell proliferative capacity and rarity in the tissues leading to limited MSCs,gradual loss of differentiation during in vitro expansion reducing the efficacy of MSC application,and variation among donors increasing the uncertainty of MSC efficacy,the clinical application of MSCs has been greatly hampered.MSCs derived from human pluripotent stem cells(hPSC-MSCs)can circumvent these problems associated with primary MSCs.Due to the infinite selfrenewal of hPSCs and their differentiation potential towards MSCs,hPSC-MSCs are emerging as an attractive alternative for regenerative medicine.This review summarizes the progress on derivation of MSCs from human pluripotent stem cells,disease modelling and drug screening using hPSC-MSCs,and various applications of hPSC-MSCs in regenerative medicine.In the end,the challenges and concerns with hPSC-MSC applications are also discussed.

Regenerative medicine using dental pulp stem cells for liver diseases

Acute liver failure is a refractory disease and its pro-gnosis, if not treated using liver transplantation, is extremely poor. It is a good candidate for regenerative medicine, where stem cell-based therapies play a central role. Mesenchymal stem cells(MSCs) are known to differentiate into multiple cell lineages including hepatocytes. Autologous cell transplant without any foreign gene induction is feasible using MSCs, thereby avoiding possible risks of tumorigenesis and immune rejection. Dental pulp also contains an MSC population that differentiates into hepatocytes. A point worthy of special mention is that dental pulp can be obtained from deciduous teeth during childhood and can be subsequently harvested when necessary after deposition in a tooth bank. MSCs have not only a regenerative capacity but also act in an anti--inflammatory manner via paracrine mechanisms. Promising efficacies and difficulties with the use of MSC derived from teeth are summarized in this review.

Dental-derived stem cells and biowaste biomaterials:What’s next in bone regenerative medicine applications

The human teeth and oral cavity harbor various populations of mesenchymal stem cells(MSCs),so called dental-derived stem cells(D-dSCs)with self-renewing and multilineage differentiation capabilities.D-dSCs properties involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment.Altogether,this viewpoint develops a general picture of current innovative strategies to employ D-dSCs combined with biomaterials and bioactive factors for regenerative medicine purposes,and offers information regarding the available scientific data and possible applications.

Generation of patient-specific pluripotent stem cells and directed differentiation of embryonic stem cells for regenerative medicine

Embryonic stem（ES） cells are pluripotent cells that can give rise to derivatives of all three embryonic germ layers. Due to its characteristics, the patient-specific ES cells are of great potential for transplantation therapies. Several strategies can reprogramme somatic cells back to pluripotent stem cells： nuclear transfer, fusion with ES cells, treatment with cell extract and induction by specific factors. Considering the future clinical use, the differentiation from ES to neurons, cardiomyocytes and many other types of cells currently provide basic cognition and experience to regenerative medicine. This article will review two courses, the reprogramming of differentiated cells and the differentiation of ES cells to specific cell types.

Dental Pulp Stem Cells, a New Era in Regenerative Medicine: A Literature Review

Objectives: The aim of this review is to explain the role of Dental Pulp Stem Cells (DPSCs) in repairing or regenerating damaged tissue/organs for both systemic and oral diseases and, in addition, review the differentiation, isolation of dental pulp stem cells and their applications in regenerative medicine. Materials and Methods: An electronic search was done using Cohchrane, PubMed and Google Scholar. Out of 310 articles, only 25 articles have been selected to be included in this review because it is directly related to the topic and they are matching the inclusion criteria of this review: “Language: English” and “Year: 2006-2016”. Results: DPSCs have been widely used as a mesenchymal stem cells source due to easy accessibility and less invasive harvesting. DPSCs could be used for pulpal regeneration, tooth reconstruction, endocrinology, neurology, angiogenesis and vasculogenises. The most common application of DPSCs in the dental field is pulp regeneration. Conclusion: Stem cell-based therapy holds a great promise to solve health problems from both systemic and oral diseases. Studying in DPSCs grows rapidly;however, there are still questionable issues needed to be optimized and answered such as the variable biological capacity of DPSCs.

Advances in Regenerative Medicine: From Stem Cells to Organoids

Stem cells have moved from lab to bedside, and many initial studies showed promising results. Therefore big companies are entering the business. However, most initial studies did not used controls to make sure of the efficacy of stem cells. Many phase-1 studies showed safety of stem cell therapies, when precaution measures were adapted. However, efficacy needs to be proven by randomized controlled trials (RCT) to exclude placebo effects. Recently, various RCTs for various conditions have been done with various contradictory results. Therefore, a meta-analysis is very useful to know whether a stem cell therapy really work for a certain condition. As various centres used various type of stem cells, various dose, and route of application, as well as different outcome measures with various results for one certain condition, sometimes it is difficult to conduct a meta-analysis when there is high heterogeneity, which is like pooling “apples” with “oranges” and “avocado” that will lead to a misleading conclusion. In many cases, where the studies are highly heterogeneous, and the heterogeneity can’t be identified, then a descriptive systematic review is the best solution to take a conclusion which protocol is the best and valuable to be standardized. Formerly it was believed that stem cells that are given to patients work by differentiating into the needed cells, and thus replacing damaged cell. However, recent evidence showed that only a few stem cells homed to the desired area, while a large amount went to various areas that were remote from the damaged area. Even though they were trapped in remote areas, the stem cells still exerted beneficial effects by remote signalling and secretion of various beneficial factors. Therefore, there are attempts to produce stem cell secretomes/metabolites to replace the stem cells, as metabolites are easier to handle and transported compared to the cells themselves. In addition, various studies worked on substitute tissue/organs “ex vivo” to be transplanted to replace a damaged organ. There are various means to produce a tissue/an organ/organoid “ex vivo” (tissue engineering) by using various stem cells, scaffold, and soluble factors, in various vessels from static vessel to bioreactors, and “on chips”. Though these attempts are in the initial stage, but some translational animal studies have been done. A more usual use of these “ex vivo” developed tissues/organs/organoids is for drug testing, such as toxicity testing, and for studying the mechanism of certain diseases that is directed toward the development of a cure of the diseases. In conclusion, many stem cell therapies have entered RCTs, but no standardized and approved protocol has been established, while organoids are usually used for drug testing and studying the mechanism of certain diseases.

The versatility of mesenchymal stem cells:From regenerative medicine to COVID,what is next?

Mesenchymal stem cells(MSCs)play key roles in regenerative medicine by promoting tissue healing.MSCs can be isolated from different adult tissues and they are able to differentiate into several lineages.Due to their antiinflammatory,angiogenic and immune-modulatory properties,MSCs are suitable for tissue engineering applications and,when associated with biomaterials,their benefits can be improved.Moreover,recently,MSCs have been studied for new clinical applications,such as in the treatment of patients with COVID-19.MSCs regenerative potential has been attributed to their secretome,which comprises extracellular matrix,soluble proteins and several elements,including the release of extracellular vesicles.Even though,in order to explore all their therapeutic potential,it is still necessary to advance in the investigation of their basic cell biology characteristics.

Mesenchymal stem cells,the secretome and biomaterials:Regenerative medicine application

Mesenchymal stem cells(MSCs)are multipotent cells usually isolated from bone marrow,endometrium,adipose tissues,skin,and dental pulp.MSCs played a crucial role in regenerative therapy and have been introduced as an interdisciplinary field between cell biology and material science.Recently,MSCs have been widely explored for their application in regenerative medicine and COVID-19 treatment.Different approaches to evaluate the future of biomaterials and stem cell properties have been developed.However,misconceptions and ethical issues still exist,such as MSCs being non-angiogenic,anti-apoptotic,and immunoregulatory competencies.Embryonic stem cells isolation primarily requires the consent of donors and can include the killing of fertilized eggs.These issues generate questions related to ethical and moral issues.However,MSCs have gained considerable attention for tissue regeneration owing to their differentiation ability with immunomodulatory effects.They are capable of secreting a broad range of biomolecules such as proteins,nucleic acids,exosomes,microRNAs,and membrane vesicles,collectively known as secretomes.Secretomes are released in response to the surrounding microenvironment.In this article,we briefly address topics related to the therapeutic potential of MSCs as an advanced approach in the field of regenerative medicine and various perspectives.

Exosomes from adipose tissue-derived stem/stromal cells:A key to future regenerative medicine

Advances in regenerative medicine correlate strongly with progress in the use of adipose tissue-derived mesenchymal stem/stromal cells.The range of therapeutic indications has also expanded over recent years.Numerous recent studies have highlighted the primary importance of paracrine secretion by these cells.Though it is interesting to compare the different types of such secretions,we believe that exosomes(extra-cellular vesicles possessing the same properties as their source cells)will likely be the main key in tomorrow’s cell therapy.Exosomes also have many advantages compared to the direct use of cells,making these particles amajor target in fundamental and translational research.

Stem cells therapy for regenerative medicine:Principles of present and future practice

The characterization and isolation of various stem cell populations, from embryonic to tissue-derived stem cells and induced pluripotent stem cells (iPSCs), have led to a rapid growth in the field of stem cell research and its potentially clinical application in the field of regenerative medicine and tissue repair. Stem cell therapy has recently progressed from the preclinical to the early clinical trial arena for a variety of diseases states, although further knowledge on action mechanisms, long-term safety issues, and standardization and characterization of the therapeutic cell products remains to be thoroughly elucidated. In this paper we summarize the current state of the art of basic and clinical research that were highlighted at the 2012 meeting of the Spanish Cell Therapy Network. This includes the current research involving in genomic and transcriptomic characterization of selected stem cell populations, studies of the role of resident and transplanted stem cells during tissue regeneration and their mechanism of action, improved new strategies of tissue engineering, transplantation of mesenchymal stem cells (MSCs) in different animal models of disease, disease correction by iPSCs, and preliminary results of cell therapy in human clinical trials.

Cell replacement with stem cell-derived retinal ganglion cells from different protocols

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

Optimizing stem cells for cardiac repair:Current status and new frontiers in regenerative cardiology

Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the postischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit andstrategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel "pharmacooptimizer" as well as genetic modifications.

Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine

Mesenchymal stem cells(MSCs)are multipotent stem cells with marked potential for regenerative medicine because of their strong immunosuppressive and regenerative abilities.The therapeutic effects of MSCs are based in part on their secretion of biologically active factors in extracellular vesicles known as exosomes.Exosomes have a diameter of 30-100 nm and mediate intercellular communication and material exchange.MSC-derived exosomes(MSC-Exos)have potential for cell-free therapy for diseases of,for instance,the kidney,liver,heart,nervous system,and musculoskeletal system.Hence,MSC-Exos are an alternative to MSCbased therapy for regenerative medicine.We review MSC-Exos and their therapeutic potential for a variety of diseases and injuries.

Protecting the delivery of heart failure: Regenerative Medicine/Stem Cell Therapeutics:Potential protections afforded by the Department of Health and Human Services and Health Resources Service Administration’s Bureau of Special Programs

Advances in stem cell science and potential clinical applications have brought clinical medicine closer to the actualization of Regenerative Medicine—an extension of transplantation of organs and cells and implantation of bioprosthetics and biodevices. The goal of such therapeutics will be intervention prior to onset of severe individual disability, enhance organ function and enhance patient performance status without incurring the economic impacts of standard organ transplantation. Regenerative Medicine is already demonstrating proof of principle or efficacy in restora- tion of myocardial contractility, joint mobility and function, immune competence, pulmonary function, immunologic self- tolerance, motor function and normal hemoglobin production with the next targets—diabetes mellitus (type I and type II), neurologic injury, hepatic dysfunction preparing to enter trials. Expenditures on health care needs of an aging U.S. citizenry approximate 20-25% ($3 trillion) of U.S. GDP currently and may to grow to 40% of U.S. GDP by 2025. As the potential of Regenerative Medicine is clinically realized, the societal impact and economic benefits will be disproportionately magnified in the economies of industrialized nations. The experi- ence of the Department of Health and Human Services (HHS), United Network for Organ Sharing (UNOS), the National Bone Marrow Donor Registry (NBMDR), and the National Vaccine Injury Compensation Programs (NVICP) can help ensure that as Regenerative Medicine strives to achieve clinical benefits while avoiding decimation of therapeutic options by product liability and medical malpractice concerns—concerns that crippled the U.S. vaccine manufacturing industry until the creation of the NVICP. The first 50 years of organ/cell/tissue transplantation demonstrates that clinical reality of allogeneic and autologous transplantation can antedate complete understanding of the basic science underlying successful transplantation. Product liability and medical malpractice liability have not impeded the development and growth of organ/cell/tissue transplanta- tion despite increased risks of infection, malignancy and cardiovascular disease in transplant recipients. Currently, human transplantation is only performed using FDA/CBER-approved, non-embryonic stem cells from peripheral blood, bone marrow or umbilical cord blood. Federal legislation passed in 2005 (HR2520 and S1317: The Bone Marrow and Cord Blood Cell Transplantation Program) authorizes the Secretary of Health and Human Services acting through the Director of HRSA to ensure uniform stem cell units distribution and outcomes monitoring via the federally-designated C.W. Bill Young Cell Transplant Program. Historically in the U.S., human biological therapies (vaccines, organ transplant and stem cell transplant) have re- quired federal protections to ensure continued distribution, fair access and avoidance of inhibitory product liability via protections afforded under the “stewardship” of the Secretary of Health and Human Services. The National Childhood Vaccine Injury Act of 1986 established the NVICP to equitably and expeditiously compensate individuals, or families of individuals, who have been declared injured by vaccines, thereby stabilizing a once imperiled vaccine supply by substan-tially reducing the threat of liability for vaccine companies, physicians, and other health care professionals who administer vaccines. Vaccines were the first biologics administered to U.S. citizens en masse and presage stem cell therapeutics (which may similarly be administered to millions) will similarly necessitate that a Stem Cell Injury Compensation Program (SCICP) will also need to be in place to demonstrate an intention to do good, an understanding that industry may do well, but that the health care consumer has a right of protection—all recognized from the outset. The Federal Tort Claims Act (FTCA) addresses liability claims via the Executive, Judicial and Legislative branches of Government, providing an um- brella of liability protection to other participants in the stem cell unit “chain of custody” under the FTCA—similar to the protection from product liability seen in organ and stem cell transplantation for the past 40-50 years. Efficacious development of regenerative medicine capabilities will mandate controlled access must first be provided for individuals with life-threatening diseases without therapeutic options or unable to benefit from or receive proven therapeutic options (ALS, cardiomyopathy and deemed not a candidate for heart transplantation, IDDM with hypoglyce- mic unawareness and no allogeneic source of traditional islet cell replacement available via HRSA) and mandates the prompt adoption of business and legal principles to ensure that the fate of the vaccine manufacturing industry does not become the fate of the stem cell therapeutics industry. If legal and regulatory concerns consume an increasing percentage of health care dollars that could be focused upon innovation, the Regenerative Medicine model will have not realized its full potential. The Diabetes Transplantation/Regenerative Medicine Model is the first organ to cell transplant model outside of oncology to demonstrate the regenerative medicine paradigm. Since all human tissues can be already recapitulated by human stem cells and key patent holders already exist, outlet or distribution of “more-than-minimally-manipulated stem cell units” as an IND approved under FDA/CBER guidelines can be accomplished via the current HHS/HRSA/Dept of Trans- plant methodology. As cardiovascular stem cell researchers develop human therapeutics utilizing more-than-minimally- manipulated stem cell products, they could be afforded protections from product liability historically enjoyed by the transplant community. Extending the Diabetes Transplant/Regenerative Medicine Model to the more than 5 million Americans with chronic heart failure, cell-based therapies to regenerate myocardial contractility could fill an existing void and be delivered in conjunction with and consistent with existing distribution of organs and tissues via HRSA/Department of Transplantation.

Mesenchymal stem cells: A promising therapeutic avenue for nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)is a pressing global health concern that is associated with metabolic syndrome and obesity.On the basis of the insights provided by Jiang et al,this editorial presents an exploration of the potential of mesenchymal stem cells(MSCs)for NAFLD treatment.MSCs have numerous desirable characteristics,including immunomodulation,anti-inflammatory pro-perties,and tissue regeneration promotion,rendering them attractive candidates for NAFLD treatment.Recent preclinical and early clinical studies have high-lighted the efficacy of MSCs in improving liver function and reducing disease severity in NAFLD models.However,MSC heterogeneity,long-term safety concerns,and unoptimized therapeutic protocols remain substantial challenges.Addressing these challenges through standardized protocols and rigorous clinical trials is essential to the safe and successful application of MSCs in NAFLD mana-gement.Continued research into MSC mechanisms and therapeutic optimization is required to improve treatments for NAFLD and related liver diseases.

Refining adipose-derived stem cell isolation for optimal regenerative therapy

This article highlights the importance of optimizing the techniques used for isolating stromal vascular fraction cells from adipose tissue.Furthermore,by presenting key findings from the literature,it clarifies the effects of refined techniques on regenerative medicine and advocates for ongoing research and innovation to enhance therapeutic outcomes.