Use of priming strategies to advance the clinical application of mesenchymal stromal/stem cell-based therapy

Mesenchymal stromal/stem cells(MSCs)have garnered significant attention in the field of regenerative medicine due to their remarkable therapeutic potential.MSCs play a pivotal role in maintaining tissue homeostasis and possess diverse functions in tissue repair and recovery in various organs.These cells are charac-terized by easy accessibility,few ethical concerns,and adaptability to in vitro cultures,making them a valuable resource for cell therapy in several clinical conditions.Over the years,it has been shown that the true therapeutic power of MSCs lies not in cell engraftment and replacement but in their ability to produce critical paracrine factors,including cytokines,growth factors,and exosomes(EXOs),which modulate the tissue microenvironment and facilitate repair and regeneration processes.Consequently,MSC-derived products,such as condi-tioned media and EXOs,are now being extensively evaluated for their potential medical applications,offering advantages over the long-term use of whole MSCs.However,the efficacy of MSC-based treatments varies in clinical trials due to both intrinsic differences resulting from the choice of diverse cell sources and non-standardized production methods.To address these concerns and to enhance MSC therapeutic potential,researchers have explored many priming strategies,including exposure to inflammatory molecules,hypoxic conditions,and three-dimensional culture techniques.These approaches have optimized MSC secretion of functional factors,empowering them with enhanced immunomodulatory,angiogenic,and regenerative properties tailored to specific medical conditions.In fact,various priming strategies show promise in the treatment of numerous diseases,from immune-related disorders to acute injuries and cancer.Currently,in order to exploit the full therapeutic potential of MSC therapy,the most important challenge is to optimize the modulation of MSCs to obtain adapted cell therapy for specific clinical disorders.In other words,to unlock the complete potential of MSCs in regenerative medicine,it is crucial to identify the most suitable tissue source and develop in vitro manipulation protocols specific to the type of disease being treated.

Fortuitous benefits of activity-based rehabilitation in stem cell-based therapy for spinal cord repair: enhancing graft survival

Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disruption of axonal connections,and demyelination of spared axons,all of which can contribute more or less to debilitating functional impairments found in patients with spinal cord injury.

The potential of stem cell-based therapy for retinal repair

Like injured neurons in the brain or spinal cord, neurons in the retina are incapable to regenerate following injury and ultimately would lead to irreversible neuronal loss and vision impairment. Over decades, extensive effort has been made to develop strategies to protect retinal neurons from death; however, the outcome is limited （Pettmann and Henderson, 1998; Bahr, 2000; Lagali and Picketts, 2011）. Replacing the degenerated retinal neurons by newly generated and functional neurons would be an ideal scenario. The rapid development of stem cell biology has recently demonstrated that stem cells could be a potential source of cells for cell replace- ment therapy because these cells have the self-renewal capacity and could be differentiated into many cell types. This review will dis- cuss the therapeutic potential of stem cell-based therapy to retinal degenerative diseases.

Cytokine interplay among the diseased retina, inflammatory cells and mesenchymal stem cells-a clue to stem cell-based therapy

Retinal degenerative disorders,such as diabetic retinopathy,retinitis pigmentosa,age-related macular degeneration or glaucoma,represent the most common causes of loss of vision and blindness.In spite of intensive research,treatment options to prevent,stop or cure these diseases are limited.Newer therapeutic approaches are offered by stem cell-based therapy.To date,various types of stem cells have been evaluated in a range of models.Among them,mesenchymal stem/stromal cells(MSCs)derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases.MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repairpromoting/regenerative effects on retinal cells.However,MSCs also produce numerous factors that could have negative impacts on retinal regeneration.The secretory activity of MSCs is strongly influenced by the cytokine environment.Therefore,the interactions among the molecules produced by the diseased retina,cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases.Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs,and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.

Biomaterial application strategies to enhance stem cell-based therapy for ischemic stroke

BACKGROUND Ischemic stroke is a condition in which an occluded blood vessel interrupts blood flow to the brain and causes irreversible neuronal cell death.Transplantation of regenerative stem cells has been proposed as a novel therapy to restore damaged neural circuitry after ischemic stroke attack.However,limitations such as low cell survival rates after transplantation remain significant challenges to stem cellbased therapy for ischemic stroke in the clinical setting.In order to enhance the therapeutic efficacy of transplanted stem cells,several biomaterials have been developed to provide a supportable cellular microenvironment or functional modification on the stem cells to optimize their reparative roles in injured tissues or organs.AIM To discuss state-of-the-art functional biomaterials that could enhance the therapeutic potential of stem cell-based treatment for ischemic stroke and provide detailed insights into the mechanisms underlying these biomaterial approaches.METHODS The PubMed,Science Direct and Scopus literature databases were searched using the keywords of“biomaterial”and“ischemic stroke”.All topically-relevant articles were then screened to identify those with focused relevance to in vivo,in vitro and clinical studies related to“stem cells”OR“progenitor cells”OR“undifferentiated cells”published in English during the years of 2011 to 2022.The systematic search was conducted up to September 30,2022.RESULTS A total of 19 articles matched all the inclusion criteria.The data contained within this collection of papers comprehensively represented 19 types of biomaterials applied on seven different types of stem/progenitor cells,namely mesenchymal stem cells,neural stem cells,induced pluripotent stem cells,neural progenitor cells,endothelial progenitor cells,neuroepithelial progenitor cells,and neuroblasts.The potential major benefits gained from the application of biomaterials in stem cell-based therapy were noted as induction of structural and functional modifications,increased stem cell retention rate in the hostile ischemic microenvironment,and promoting the secretion of important cytokines for reparative mechanisms.CONCLUSION Biomaterials have a relatively high potential for enhancing stem cell therapy.Nonetheless,there is a scarcity of evidence from human clinical studies for the efficacy of this bioengineered cell therapy,highlighting that it is still too early to draw a definitive conclusion on efficacy and safety for patient usage.Future in-depth clinical investigations are necessary to realize translation of this therapy into a more conscientious and judicious evidence-based therapy for clinical application.

Stem cell-based ischemic stroke therapy:Novel modifications and clinical challenges

Ischemic stroke(IS)causes severe disability and high mortality worldwide.Stem cell(SC)therapy exhibits unique therapeutic potential for IS that differs from current treatments.SC’s cell homing,differentiation and paracrine abilities give hope for neuroprotection.Recent studies on SC modification have enhanced therapeutic effects for IS,including gene transfection,nanoparticle modification,biomaterial modification and pretreatment.Thesemethods improve survival rate,homing,neural differentiation,and paracrine abilities in ischemic areas.However,many problems must be resolved before SC therapy can be clinically applied.These issues include production quality and quantity,stability during transportation and storage,as well as usage regulations.Herein,we reviewed the brief pathogenesis of IS,the“multi-mechanism”advantages of SCs for treating IS,various SC modification methods,and SC therapy challenges.We aim to uncover the potential and overcome the challenges of using SCs for treating IS and convey innovative ideas for modifying SCs.

The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

Cell-based therapies for limbal stem cell deficiency: a literature review

Background and Objective:Limbal stem cell deficiency(LSCD)is characterized by the insufficiency of limbal stem cells to maintain the corneal epithelium.Severe cases of LSCD may be treated with limbal transplantation from healthy autologous or allogeneic limbal tissue.Multiple cell-based therapies have been studied as alternative treatments to improve success rates and minimize immunosuppressive regimens after allogeneic transplants.In this review,we describe the success rates,and complications of different cell-based therapies for LSCD.We also discuss each therapy’s relative strengths and weaknesses,their history in animal and human studies,and their effectiveness compared to traditional transplants.Methods:PubMed was searched for publications using the terms LSCD,cell-based therapy,cultivated limbal epithelial transplantation(CLET),cultivated oral mucosal epithelial transplantation(COMET),and mesenchymal stem cells from 1989 to August 2022.Inclusion criteria were English language articles.Exclusion criteria were non-English language articles.Key Content and Findings:current cell-based therapies for LSCD are CLET and non-limbal epithelial cells.Non-limbal epithelial cell methods include COMET,conjunctival epithelial autografts,and mesenchymal stem/stromal cells(MSCs).Moreover,several alternative potential sources of non-limbal cells have described,including induced pluripotent stem cells(iPSCs),human embryonic stem cells(hESCs),human dental pulp stem cells,hair follicle bulge-derived epithelial stem cells,amniotic membrane epithelial cells,and human umbilical cord lining epithelial cells.Conclusions:Cell-based therapies are a promising treatment modality for LSCD.While CLET is currently the only approved cell-based therapy and is only approved in the European Union,more novel methods have also been shown to be effective in human or animal studies thus far.Non-limbal epithelial cells such as COMET are also an alternative treatment to allogeneic transplants especially as a surface stabilizing procedure.iPSCs are currently being studied in early phase trials and have the potential to revolutionize the way LSCD is treated.Lastly,cell-based therapies for restoring the limbal niche such as mesenchymal stem cells have also shown promising results in the first human proof-of-concept study.Several potential sources of non-limbal cells are under investigation.

Mesenchymal stem cell-based therapy for burn wound healing

Burns,with their high incidence and mortality rates,have a devastating effect on patients.There are still huge challenges in the management of burns.Mesenchymal stem cells(MSCs),which have multidirectional differentiation potential,have aroused interest in exploring the capacity for treating different intractable diseases due to their strong proliferation,tissue repair,immune tolerance and paracrine abilities,among other features.Currently,several animal studies have shown that MSCs play various roles and have beneficial effects in promoting wound healing,inhibiting burn inflammation and preventing the formation of pathological scars during burn healing process.The substances MSCs secrete can act on peripheral cells and promote burn repair.According to preclinical research,MSC-based treatments can effectively improve burn wound healing and reduce pain.However,due to the small number of patients and the lack of controls,treatment plans and evaluation criteria vary widely,thus limiting the value of these clinical studies.Therefore,to better evaluate the safety and effectiveness of MSC-based burn treatments,standardization of the application scheme and evaluation criteria of MSC therapy in burn treatment is required in the future.In addition,the combination of MSC pretreatment and dressing materials are also conducive to improving the therapeutic effect of MSCs on burns.In this article,we review current animal research and clinical trials based on the use of stem cell therapy for treating burns and discuss the main challenges and coping strategies facing future clinical applications.

Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

Application of mesenchymal stem cell therapy for premature ovarian insufficiency: Recent advances from mechanisms to therapeutics

The incidence of premature ovarian insufficiency(POI)is increasing worldwide,particularly among younger women,posing a significant challenge to fertility.In addition to menopausal symptoms,POI leads to several complications that profoundly affect female reproductive function and overall health.Unfortunately,current clinical treatment strategies for this condition are limited and often yield unsatisfactory outcomes.These approaches typically involve hormone repla-cement therapy combined with psychological support.Recently,mesenchymal stem cell(MSC)therapies for POI have garnered considerable attention in global research.MSCs can restore ovarian reproductive and endocrine functions through diverse mechanisms,including controlling differentiation,promoting angiogenesis,regulating ovarian fibrosis,inhibiting apoptosis,enhancing autocrine and paracrine effects,suppressing inflammation,modulating the immune system,and genetic regulation.This editorial offers a succinct summary of the application of MSC therapy in the context of POI,providing evidence for groundbreaking medical approaches that have potential to enhance reproductive health and overall well-being for women.

Stem cell-based therapy for erectile dysfunction

Objective To review the effect of stem cells in erectile dysfunction as well as their application to the therapy of erectile dysfunction. Data sources The data used in the present article were mainly from PubMed with relevant English articles published from 1974 to 2011. The search terms were ＂stem cells＂ and ＂erectile dysfunction＂. Study selection Articles regarding the role of stem cells in erectile dysfunction and their application to the therapy of erectile dysfunction were selected. Results Stem cells hold great promise for regenerative medicine because of their ability to self-renew and to differentiate into various cell types. Meanwhile, in preclinical experiments, therapeutic gene-modified stem cells have been approved to offer a novel strategy for cell therapy and gene therapy of erectile dysfunction. Conclusion The transplantation of stem cells has the potential to provide cell types capable of restoring normal function after injury or degradation inerectile dysfunction. However, a series of problems, such as the safety of stem cells transplantation, their application in cell therapy and gene therapy of erectile dysfunction need further investigation.

Importance of the stem cell microenvironment for ophthalmological cell-based therapy

Cell therapy is a promising treatment for diseases that are caused by cell degeneration or death. The cells for clinical transplantation are usually obtained by culturing healthy allogeneic or exogenous tissue invitro. However, for diseases of the eye, obtaining the adequate number of cells for clinical transplantation is difficult due to the small size of tissue donors and the frequent needs of long-term amplification of cells in vitro, which results in low cell viability after transplantation. In addition, the transplanted cells often develop fibrosis or degrade and have very low survival. Embryonic stem cells(ESCs) and induced pluripotent stem cells(i PS) are also promising candidates for cell therapy. Unfortunately, the differentiation of ESCs can bring immune rejection, tumorigenicity and undesired differentiated cells, limiting its clinical application. Although i PS cells can avoid the risk of immune rejection caused by ES cell differentiation post-transplantation, the low conversion rate, the risk of tumor formation and the potentially unpredictable biological changes that could occur through genetic manipulation hinder its clinical application. Thus, the desired clinical effect of cell therapy is impaired by these factors. Recent research findings recognize that the reason for low survival of the implanted cells not only depends on the seeded cells, but also on the cell microenvironment, which determines the cell survival, proliferation and even reverse differentiation. When used for cell therapy, the transplanted cells need a specific three-dimensional structure to anchor and specific extra cellular matrix components in addition to relevant cytokine signaling to transfer the required information to support their growth. These structures present in the matrix in which the stem cells reside are known as the stem cell microenvironment. The microenvironment interaction with the stem cells provides the necessary homeostasis for cell maintenance and growth. A large number of studies suggest that to explore how to reconstruct the stem cell microenvironment and strengthen its combination with the transplanted cells are key steps to successful cell therapy. In this review, we will describe the interactions of the stem cell microenvironment with the stem cells, discuss the importance of the stem cell microenvironment for cell-based therapy in ocular diseases, and introduce the progress of stem cell-basedtherapy for ocular diseases.

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 pulp stem cells: Novel cell-based and cell-free therapy for peripheral nerve repair

The regeneration of peripheral nerves comprises complicated steps involving a set of cellular and molecular events in distal nerve stumps with axonal sprouting and remyelination. Stem cell isolation and expansion for peripheral nerve repair(PNR) can be achieved using a wide diversity of prenatal and adult tissues, such as bone marrow or brain tissues. The ability to obtain stem cells for cell-based therapy(CBT) is limited due to donor site morbidity and the invasive nature of the harvesting process. Dental pulp stem cells(DPSCs) can be relatively and simply isolated from the dental pulps of permanent teeth, extracted for surgical or orthodontic reasons. DPSCs are of neural crest origin with an outstanding ability to differentiate into multiple cell lineages. They have better potential to differentiate into neural and glial cells than other stem cell sources through the expression and secretion of certain markers and a range of neurotropic factors;thus, they should be considered a good choice for PNR using CBT. In addition,these cells have paracrine effects through the secretion of neurotrophic growth factors and extracellular vesicles, which can enhance axonal growth and remyelination by decreasing the number of dying cells and activating local inhabitant stem cell populations, thereby revitalizing dormant or blocked cells,modulating the immune system and regulating inflammatory responses. The use of DPSC-derived secretomes holds great promise for controllable and manageable therapy for peripheral nerve injury. In this review, up-to-date information about the neurotrophic and neurogenic properties of DPSCs and their secretomes is provided.

Cell-based therapeutic strategies for treatment of spinocerebellar ataxias:an update

Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.

Drug-and cell-based therapies for targeting neuroinflammation in traumatic brain injury

TBI pathology： Traumatic brain injury （TBI） is caused by an external force to the head, resulting in trauma to the brain. Approximately 1.7 million Americans suffer from TBI every year. Out of the 1.7 million suffering from TBI, an estimated 52,000 injuries result in death, leaving a mass amount of peo- ple with symptoms that could last a few days, a few years, or their entire life （Faul et al., 2010）. TBI can be classified as mild, moderate and severe. Depending on the classification and the extent of the injury, TBI can cause both physical symptoms and cognitive disorders （Lozano et al., 2015）.

Biomimetic biomineralization nanoplatform-mediated differentiation therapy and phototherapy for cancer stem cell inhibition and antitumor immunity activation

Growing evidence suggests that the presence of cancer stem cells(CSCs)is a major challenge in current tumor treatments,especially the transition from non-CSCs to differentiation of CSCs for evading conventional therapies and driving metastasis.Here we propose a therapeutic strategy of synergistic differentiation therapy and phototherapy to induce differentiation of CSCs into mature tumor cells by differentiation inducers and synergistic elimination of them and normal cancer cells through phototherapy.In this work,we synthesized a biomimetic nanoplatform loaded with IR-780 and all-trans retinoic acid(ATRA)via biomineralization.This method can integrate aluminum ions into small-sized protein carriers to form nanoclusters,which undergo responsive degradation under acidic conditions and facilitate deep tumor penetration.With the help of CSC differentiation induced by ATRA,IR-780 inhibited the self-renewal of CSCs and cancer progression by generating hyperthermia and reactive oxygen species in a synergistic manner.Furthermore,ATRA can boost immunogenic cell death induced by phototherapy,thereby strongly causing a systemic anti-tumor immune response and efficiently eliminating CSCs and tumor cells.Taken together,this dual strategy represents a new paradigm of targeted eradication of CSCs and tumors by inducing CSC differentiation,improving photothermal therapy/photodynamic therapy and enhancing antitumor immunity.

Mesenchymal stem cell-and extracellular vesicle-based therapies for Alzheimer's disease:progress,advantages,and challenges

Alzheimer's disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimer's disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. Mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimer's disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunction/loss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimer's disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments.

Human pluripotent stem cell-derivedβcells:Truly immature isletβcells for type 1 diabetes therapy?

A century has passed since the Nobel Prize winning discovery of insulin,which still remains the mainstay treatment for type 1 diabetes mellitus(T1DM)to this day.True to the words of its discoverer Sir Frederick Banting,“insulin is not a cure for diabetes,it is a treatment”,millions of people with T1DM are dependent on daily insulin medications for life.Clinical donor islet transplantation has proven that T1DM is curable,however due to profound shortages of donor islets,it is not a mainstream treatment option for T1DM.Human pluripotent stem cell derived insulin-secreting cells,pervasively known as stem cell-derivedβcells(SC-βcells),are a promising alternative source and have the potential to become a T1DM treatment through cell replacement therapy.Here we briefly review how isletβcells develop and mature in vivo and several types of reported SC-βcells produced using different ex vivo protocols in the last decade.Although some markers of maturation were expressed and glucose stimulated insulin secretion was shown,the SC-βcells have not been directly compared to their in vivo counterparts,generally have limited glucose response,and are not yet fully matured.Due to the presence of extra-pancreatic insulin-expressing cells,and ethical and technological issues,further clarification of the true nature of these SC-βcells is required.