Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Bioengineering breakthroughs:The impact of stem cell models on advanced therapy medicinal product development

The burgeoning field of bioengineering has witnessed significant strides due to the advent of stem cell models,particularly in their application in advanced therapy medicinal products(ATMPs).In this review,we examine the multifaceted impact of these developments,emphasizing the potential of stem cell models to enhance the sophistication of ATMPs and to offer alternatives to animal testing.Stem cell-derived tissues are particularly promising because they can reshape the preclinical landscape by providing more physiologically relevant and ethically sound platforms for drug screening and disease modelling.We also discuss the critical challenges of reproducibility and accuracy in measurements to ensure the integrity and utility of stem cell models in research and application.Moreover,this review highlights the imperative of stem cell models to align with regulatory standards,ensuring using stem cells in ATMPs translates into safe and effective clinical therapies.With regulatory approval serving as a gateway to clinical adoption,the collaborative efforts between scientists and regulators are vital for the progression of stem cell applications from bench to bedside.We advocate for a balanced approach that nurtures innovation within the framework of rigorous validation and regulatory compliance,ensuring that stem cell-base solutions are maximized to promote public trust and patient health in ATMPs.

Application of stem cells in tissue engineering for defense medicine

The dynamic nature of modern warfare,including threats and injuries faced by soldiers,necessitates the development of countermeasures that address a wide variety of injuries.Tissue engineering has emerged as a field with the potential to provide contemporary solutions.In this review,discussions focus on the applications of stem cells in tissue engineering to address health risks frequently faced by combatants at war.Human development depends intimately on stem cells,the mysterious precursor to every kind of cell in the body that,with proper instruction,can grow and differentiate into any new tissue or organ.Recent reports have suggested the greater therapeutic effects of the anti-inflammatory,trophic,paracrine and immune-modulatory functions associated with these cells,which induce them to restore normal healing and tissue regeneration by modulating immune reactions,regulating inflammation,and suppressing fibrosis.Therefore,the use of stem cells holds significant promise for the treatment of many battlefield injuries and their complications.These applications include the treatment of injuries to the skin,sensory organs,nervous system tissues,the musculoskeletal system,circulatory/pulmonary tissues and genitals/testicles and of acute radiation syndrome and the development of novel biosensors.The new research developments in these areas suggest that solutions are being developed to reduce critical consequences of wounds and exposures suffered in warfare.Current military applications of stem cell-based therapies are already saving the lives of soldiers who would have died in previous conflicts.Injuries that would have resulted in deaths previously now result in wounds today;similarly,today’s permanent wounds may be reduced to tomorrow’s bad memories with further advances in stem cell-based therapies.

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.

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.

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.

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.

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.

Clinical trial with traditional Chinese medicine intervention ''tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment'' for chronic hepatitis B-associated liver failure

AIM:To study the clinical efficacy of traditional Chinese medicine(TCM)intervention"tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment"("TTK")for treating liver failure due to chronic hepatitis B.METHODS:We designed the study as a randomized controlled clinical trial.Registration number of Chinese Clinical Trial Registry is Chi CTR-TRC-12002961.A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study.Participants were randomly assigned to the following three groups:(1)a modern medicine control group(MMC group,36patients);(2)a"tonifying qi and detoxification"("TQD")group(72 patients);and(3)a"tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment"("TTK")group(36patients).Patients in the MMC group received general internal medicine treatment;patients in the"TQD"group were given a TCM formula"tonifying qi and detoxification"and general internal medicine treatment;patients in the"TTK"group were given a TCM formula of"TTK"and general internal medicine treatment.All participants were treated for 8 wk and then followed at 48 wk following their final treatment.The primaryefficacy end point was the patient fatality rate in each group.Measurements of various virological and biochemical indicators served as secondary endpoints.The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups.RESULTS:At the 48-wk post-treatment time point,the patient fatality rates in the MMC,"TQD",and"TTK"groups were 51.61%,35.38%,and 16.67%,respectively,and the differences between groups were statistically significant(P<0.05).However,there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups(P>0.05).Patients in the"TTK"group had significantly higher levels of serum total bilirubin compared to MMC subjects(339.40μmol/L±270.09μmol/L vs 176.13μmol/L±185.70μmol/L,P=0.014).Serum albumin levels were significantly increased in both the"TQD"group and"TTK"group as compared with the MMC group(31.30 g/L±4.77g/L,30.72 g/L±2.89 g/L vs 28.57 g/L±4.56 g/L,P<0.05).There were no significant differences in levels of alanine transaminase among the three groups(P>0.05).Safety data showed that there was one case of stomachache in the"TQD"group and one case of gastrointestinal side effect in the"TTK"group.CONCLUSION:Treatment with"TTK"improved the survival rates of patients with liver failure due to chronic hepatitis B.Additionally,liver tissue was regenerated and liver function was restored.

Comprehensive regulation of traditional Chinese medicine on proliferation and differentiation of neural stem cells

Since the diccovery of neural stem cells(NSCs)in the embryonic and adult mammalian central nerous system,it provided novel ideas forneurogenesis as the potential of proliferation and differentiation of NSCs.One of the ways to promote the clinical application of neural stem cells(NSCs)is searching effective methods which regulate the proliferation and differentiation.This is also a problem urgently to be solved in medical field.Plenty of earlier studies have shown that traditional chinese medicine can promote the proliferation and differentiation of NSCs by regulating the related signaling pathway in vivo and in vitro.The reports of Chinese and foreign literatures on regulating the proliferation and differentiation of neural stem cells in recent ten years and their target and signaling pathways is analyzed in this review.The traditional chinese medicine regulate proliferation and differentiation of NSCs by the signaling pathways of Notch,PI3K/Akt,Wnt/β-catenin,and GFs.And,those signaling pathways have cross-talk in the regulation progress.Moreover,some traditional Chinese medicine,such as astragalus,has a variety of active ingredients to regulate proliferation and differentiation of NSCs through different signaling pathways.However,to accelerate the clinical application of neural stem cells,the studies aboutthe proliferation and differentiation of NSCs and Chinese medicine should be further deepened,the mechanism of multiple targets and the comprehensive regulation function of traditional Chinese medicine should be clarified.

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.

Recent trends in stem cell-based therapies and applications of artificial intelligence in regenerative medicine

Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity.This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cellbased therapies.Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal.In this review,the recent advances in stem cell-based therapies in regenerative medicine are discussed,emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use.Recent applications of artificial intelligence algorithms in stem cell-based therapies,their limitation,and future prospects are highlighted.

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.

Psychological Issues for Patients Undergoing Stem Cell Therapy and Regenerative Medicine

Stem cell therapy is a relatively new treatment modality in the field of regenerative medicine. The therapy is gaining increased awareness and acceptance by the public. There are multiple factors that contribute to a stem cell procedure for regenerative medicine in order for it to be successful. One of these factors is a patient’s mental health and psychological state. The role and significance of a counsellor/psychologist will be examined as a crucial part of the regenerative medicine team. Pre-existing issues of depression, anxiety, post-traumatic stress disorder (PTSD), addiction, low self-esteem and high levels of stress could adversely affect outcomes. For example, fears and phobias are counter-productive for planned regenerative therapy. The counsellor must also assess and determine that the patient is mentally and psychologically healthy. In addition, advice is necessary for the patient to have realistic expectations in order for them to be eligible for treatment. Some patients are not suitable for stem cells and other regenerative procedures until psychological treatment is successful, particularly in body image dysmorphia. A comprehensive psychological assessment is needed and answers must be provided for patients by the counsellor during all phases of the treatment.

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.

Banking of perinatal mesenchymal stem/stromal cells for stem cellbased personalized medicine over lifetime:Matters arising

Mesenchymal stromal/stem cells(MSCs)are currently applied in regenerative medicine and tissue engineering.Numerous clinical studies have indicated that MSCs from different tissue sources can provide therapeutic benefits for patients.MSCs derived from either human adult or perinatal tissues have their own unique advantages in their medical practices.Usually,clinical studies are conducted by using of cultured MSCs after thawing or short-term cryopreserved-then-thawed MSCs prior to administration for the treatment of a wide range of diseases and medical disorders.Currently,cryogenically banking perinatal MSCs for potential personalized medicine for later use in lifetime has raised growing interest in China as well as in many other countries.Meanwhile,this has led to questions regarding the availability,stability,consistency,multipotency,and therapeutic efficiency of the potential perinatal MSC-derived therapeutic products after longterm cryostorage.This opinion review does not minimize any therapeutic benefit of perinatal MSCs in many diseases after short-term cryopreservation.This article mainly describes what is known about banking perinatal MSCs in China and,importantly,it is to recognize the limitation and uncertainty of the perinatal MSCs stored in cryobanks for stem cell medical treatments in whole life.This article also provides several recommendations for banking of perinatal MSCs for potentially future personalized medicine,albeit it is impossible to anticipate whether the donor will benefit from banked MSCs during her/his lifetime.