Prospects for translational regenerative medicine

Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.     

Current status and prospects of organoid-based regenerative medicine

Organoids derived from stem cells or organ-specific progenitors are self-organizable, self-renewable, and multicellular three-dimensional (3D) structures that can mimic the function and structure of the derived tissue. Due to such characteristics, organoids are attracting attention as an excellent ex vivo model for drug screening at the stage of drug development. In addition, since the applicability of organoids as therapeutics for tissue regeneration has been embossed, the development of various organoids-based regenerative medicine has been rapidly progressing, reaching the clinical trial stage. In this review, we give a general overview of organoids and describe current status and prospects of organoid-based regenerative medicine, focusing on organoid-based regenerative therapeutics currently under development including clinical trials.     

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.     

Nanofat: A therapeutic paradigm in regenerative medicine

Adipose tissue is a compact and well-organized tissue containing a heterogeneous cellular population of progenitor cells, including mesenchymal stromal cells. Due to its availability and accessibility, adipose tissue is considered a “stem cell depot.” Adipose tissue products possess anti-inflammatory, anti-fibrotic, anti-apoptotic, and immunomodulatory effects. Nanofat, being a compact bundle of stem cells with regenerative and tissue remodeling potential, has potential in translational and regenerative medicine. Considering the wide range of applicability of its reconstructive and regenerative potential, the applications of nanofat can be used in various disciplines. Nanofat behaves on the line of adipose tissue-derived mesenchymal stromal cells. At the site of injury, these stromal cells initiate a site-specific reparative response comprised of remodeling of the extracellular matrix, enhanced and sustained angiogenesis, and immune system modulation. These properties of stromal cells provide a platform for the usage of regenerative medicine principles in curbing various diseases. Details about nanofat, including various preparation methods, characterization, delivery methods, evidence on practical applications, and ethical concerns are included in this review. However, appropriate guidelines and preparation protocols for its optimal use in a wide range of clinical applications have yet to be standardized.     

Multiplexed targeting of microRNA in stem cell-derived extracellular vesicles for regenerative medicine

Regenerative medicine is a research field that develops methods to restore damaged cell or tissue function by regeneration, repair or replacement. Stem cells are the raw material of the body that is ultimately used from the point of view of regenerative medicine, and stem cell therapy uses cells themselves or their derivatives to promote responses to diseases and dysfunctions, the ultimate goal of regenerative medicine. Stem cell-derived extracellular vesicles (EVs) are recognized as an attractive source because they can enrich exogenous microRNAs (miRNAs) by targeting pathological recipient cells for disease therapy and can overcome the obstacles faced by current cell therapy agents. However, there are some limitations that need to be addressed before using miRNA-enriched EVs derived from stem cells for multiplexed therapeutic targeting in many diseases. Here, we review various roles on miRNA-based stem cell EVs that can induce effective and stable functional improvement of stem cell-derived EVs. In addition, we introduce and review the implications of several miRNA-enriched EV therapies improved by multiplexed targeting in diseases involving the circulatory system and nervous system. This systemic review may offer potential roles for stem cell-derived therapeutics with multiplexed targeting.     

Stem cell-biomaterial interactions for regenerative medicine

The synergism of stem cell biology and biomaterial technology promises to have a profound impact on stem-cell-based clinical applications for tissue regeneration. Biomaterials development is rapidly advancing to display properties that, in a precise and physiological fashion, could drive stem-cell fate both in vitro and in vivo. Thus, the design of novel materials is trying to recapitulate the molecular events involved in the production, clearance and interaction of molecules within tissue in pathologic conditions and regeneration of tissue/organs. In this review we will report on the challenges behind translating stem cell biology and biomaterial innovations into novel clinical therapeutic applications for tissue and organ replacements (graphical abstract).     

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 cell-based 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.     

Perivascular cells for regenerative medicine

Mesenchymal stem/stromal cells (MSC) are currently the best candidate therapeutic cells for regenerative medicine related to osteoarticular, muscular, vascular and inflammatory diseases, although these cells remain heterogeneous and necessitate a better biological characterization. We and others recently described that MSC originate from two types of perivascular cells, namely pericytes and adventitial cells and contain the in situ counterpart of MSC in developing and adult human organs, which can be prospectively purified using well defined cell surface markers. Pericytes encircle endothelial cells of capillaries and microvessels and express the adhesion molecule CD146 and the PDGFRβ, but lack endothelial and haematopoietic markers such as CD34, CD31, vWF (von Willebrand factor), the ligand for Ulex europaeus 1 (UEA1) and CD45 respectively. The proteoglycan NG2 is a pericyte marker exclusively associated with the arterial system. Besides its expression in smooth muscle cells, smooth muscle actin (αSMA) is also detected in subsets of pericytes. Adventitial cells surround the largest vessels and, opposite to pericytes, are not closely associated to endothelial cells. Adventitial cells express CD34 and lack αSMA and all endothelial and haematopoietic cell markers, as for pericytes. Altogether, pericytes and adventitial perivascular cells express in situ and in culture markers of MSC and display capacities to differentiate towards osteogenic, adipogenic and chondrogenic cell lineages. Importantly, adventitial cells can differentiate into pericyte‐like cells under inductive conditions in vitro. Altogether, using purified perivascular cells instead of MSC may bring higher benefits to regenerative medicine, including the possibility, for the first time, to use these cells uncultured.     

胚胎干细胞技术的研究进展

干细胞可以分为成体干细胞和胚胎干细胞两类,是当前生物医学领域的一个热点。由于干细胞在医学领域有巨大应用前景,世界各国都对此给予了相当的重视;投入大量资金支持本国的科学家从事干细胞的科学研究。目前,干细胞的研究还处于试验室阶段,很多技术难题还没有解决,尤其是胚胎干细胞的不定向分化问题,以及一些伦理方面的争议。宗教界人士和社会论理学方面的人士对于干细胞的研究还有异议。集中论述了胚胎干细胞的研究进展和医学功用。     

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 self-renewal 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.     

Stem cell- and scaffold-based tissue engineering approaches to osteochondral regenerative medicine

In osteochondral tissue engineering, cell recruitment, proliferation, differentiation, and patterning are critical for forming biologically and structurally viable constructs for repair of damaged or diseased tissue. However, since constructs prepared ex vivo lack the multitude of cues present in the in vivo microenvironment, cells often need to be supplied with external biological and physical stimuli to coax them toward targeted tissue functions. To determine which stimuli to present to cells, bioengineering strategies can benefit significantly from endogenous examples of skeletogenesis. As an example of developmental skeletogenesis, the developing limb bud serves as an excellent model system in which to study how osteochondral structures form from undifferentiated precursor cells. Alongside skeletal formation during embryogenesis, bone also possesses innate regenerative capacity, displaying remarkable ability to heal after damage. Bone fracture healing shares many features with bone development, driving the hypothesis that the regenerative process generally recapitulates development. Similarities and differences between the two modes of bone formation may offer insight into the special requirements for healing damaged or diseased bone. Thus, endogenous fracture healing, as an example of regenerative skeletogenesis, may also inform bioengineering strategies. In this review, we summarize the key cellular events involving stem and progenitor cells in developmental and regenerative skeletogenesis, and discuss in parallel the corresponding cell- and scaffold-based strategies that tissue engineers employ to recapitulate these events in vitro.     

Calcium channels and their role in regenerative medicine

Stem cells hold indefinite self-renewable capability that can be differentiated into all desired cell types.Based on their plasticity potential,they are divided into totipotent(morula stage cells),pluripotent(embryonic stem cells),multipotent(hematopoietic stem cells,multipotent adult progenitor stem cells,and mesenchymal stem cells[MSCs]),and unipotent(progenitor cells that differentiate into a single lineage)cells.Though bone marrow is the primary source of multipotent stem cells in adults,other tissues such as adipose tissues,placenta,amniotic fluid,umbilical cord blood,periodontal ligament,and dental pulp also harbor stem cells that can be used for regenerative therapy.In addition,induced pluripotent stem cells also exhibit fundamental properties of self-renewal and differentiation into specialized cells,and thus could be another source for regenerative medicine.Several diseases including neurodegenerative diseases,cardiovascular diseases,autoimmune diseases,virus infection(also coronavirus disease 2019)have limited success with conventional medicine,and stem cell transplantation is assumed to be the best therapy to treat these disorders.Importantly,MSCs,are by far the best for regenerative medicine due to their limited immune modulation and adequate tissue repair.Moreover,MSCs have the potential to migrate towards the damaged area,which is regulated by various factors and signaling processes.Recent studies have shown that extracellular calcium(Ca²⁺)promotes the proliferation of MSCs,and thus can assist in transplantation therapy.Ca²⁺signaling is a highly adaptable intracellular signal that contains several components such as cell-surface receptors,Ca²⁺channels/pumps/exchangers,Ca²⁺buffers,and Ca²⁺sensors,which together are essential for the appropriate functioning of stem cells and thus modulate their proliferative and regenerative capacity,which will be discussed in this review.     

Stem cell therapies and regenerative medicine in China

Stem cells are the core of tissue repair and regeneration,and a promising cell source for novel therapies.In recent years,research into stem cell therapies has been particularly exciting in China.The remarkable advancements in basic stem cell research and clinically effective trials have led to fresh insights into regenerative medicine,such as treatments for sweat gland injury after burns,diabetes,and liver injury.High hopes have inspired numerous experimental and clinical trials.At the same time,government investment and policy support of research continues to increase markedly.However,numerous challenges must be overcome before novel stem cell therapies can achieve meaningful clinical outcomes.     

Extracellular vesicles: Emerged as a promising strategy for regenerative medicine

Cell transplantation therapy has certain limitations including immune rejection and limited cell viability, which seriously hinder the transformation of stem cell-based tissue regeneration into clinical practice. Extracellular vesicles (EVs) not only possess the advantages of its derived cells, but also can avoid the risks of cell transplantation. EVs are intelligent and controllable biomaterials that can participate in a variety of physiological and pathological activities, tissue repair and regeneration by transmitting a variety of biological signals, showing great potential in cell-free tissue regeneration. In this review, we summarized the origins and characteristics of EVs, introduced the pivotal role of EVs in diverse tissues regeneration, discussed the underlying mechanisms, prospects, and challenges of EVs. We also pointed out the problems that need to be solved, application directions, and prospects of EVs in the future and shed new light on the novel cell-free strategy for using EVs in the field of regenerative medicine.     

Gingival-derived mesenchymal stem cells:An endless resource for regenerative dentistry

The gingiva, the masticatory portion of the oral mucosa, is excised and discarded frequently during routine dental treatments and following tooth extraction, dental crown lengthening, gingivectomy and periodontal surgeries. Subsequent to excision, healing eventually happens in a short time period after gingival surgery. Clinically, the gingival tissue can be collected very easily and, in the laboratory, it is also very easy to isolate gingival-derived mesenchymal stem cells (GMSCs) from this discarded gingival tissue. GMSCs, a stem cell population within the lamina propria of the gingival tissue, can be isolated from attached and free gingiva, inflamed gingival tissu-es, and from hyperplastic gingiva. Comparatively, they constitute more attractive alternatives to other dental-derived mesenchymal stem cells due to the availability and accessibility of gingival tissues. They have unique immunomodulatory functions and well-documented self-renewal and multipotent differentiation properties. They display positive signals for Stro-1, Oct-4 and SSEA-4 pluripotency-associated markers, with some co-expre-ssing Oct4/Stro-1 or Oct-4/SSEA-4. They should be considered as the best stem cell source for cell-based therapies and regenerative dentistry. The clinical use of GMSCs for regenerative dentistry represents an attrac-tive therapeutic modality. However, numerous biological and technical challenges need to be addressed prior to considering transplantation approaches of GMSCs as clinically realistic therapies for humans.     

Human dental pulp stem cells: Applications in future regenerative medicine

Stem cells are pluripotent cells, having a property of differentiating into various types of cells of human body. Several studies have developed mesenchymal stem cells (MSCs) from various human tissues, peripheral blood and body fluids. These cells are then characterized by cellular and molecular markers to understand their specific phenotypes. Dental pulp stem cells (DPSCs) are having a MSCs phenotype and they are differentiated into neuron, cardiomyocytes, chondrocytes, osteoblasts, liver cells and β cells of islet of pancreas. Thus, DPSCs have shown great potentiality to use in regenerative medicine for treatment of various human diseases including dental related problems. These cells can also be developed into induced pluripotent stem cells by incorporation of pluripotency markers and use for regenerative therapies of various diseases. The DPSCs are derived from various dental tissues such as human exfoliated deciduous teeth, apical papilla, periodontal ligament and dental follicle tissue. This review will overview the information about isolation, cellular and molecular characterization and differentiation of DPSCs into various types of human cells and thus these cells have important applications in regenerative therapies for various diseases. This review will be most useful for postgraduate dental students as well as scientists working in the field of oral pathology and oral medicine.     

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 3 D 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 3 D cell culture tools to maintain the stemness and expand the regenerative and differentiation capacities of mesenchymal cell lineages.     

Stem cell-based composite tissue constructs for regenerative medicine

A major task of contemporary medicine and dentistry is restoration of human tissues and organs lost to diseases and trauma. A decade-long intense effort in tissue engineering has provided the proof of concept for cell-based replacement of a number of individual tissues such as the skin, cartilage, and bone. Recent work in stem cell-based in vivo restoration of multiple tissue phenotypes by composite tissue constructs such as osteochondral and fibro-osseous grafts has demonstrated probable clues for bioengineered replacement of complex anatomical structures consisting of multiple cell lineages such as the synovial joint condyle, tendon-bone complex, bone-ligament junction, and the periodontium. Of greater significance is a tangible contribution by current attempts to restore the structure and function of multitissue structures using cell-based composite tissue constructs to the understanding of ultimate biological restoration of complex organs such as the kidney or liver. The present review focuses on recent advances in stem cell-based composite tissue constructs and attempts to outline challenges for the manipulation of stem cells in tailored biomaterials in alignment with approaches potentially utilizable in regenerative medicine of human tissues and organs.     

Mesenchymal stem cells in ischemic tissue regeneration

Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells(MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and pr...     

Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: Role of secretome and exosomes

Over the last decades, mesenchymal stem cells (MSCs) have been extensively studied with regard to their potential applications in regenerative medicine. In rheumatic diseases, MSC-based therapy is the subject of great expectations for patients who are refractory to proposed treatments such as rheumatoid arthritis (RA), or display degenerative injuries without possible curative treatment, such as osteoarthritis (OA). The therapeutic potential of MSCs has been demonstrated in several pre-clinical models of OA or RA and both the safety and efficacy of MSC-based therapy is being evaluated in humans. The predominant mechanism by which MSCs participate to tissue repair is through a paracrine activity. Via the production of a multitude of trophic factors with various properties, MSCs can reduce tissue injury, protect tissue from further degradation and/or enhance tissue repair. However, a thorough in vivo examination of MSC-derived secretome and strategies to modulate it are still lacking. The present review discusses the current understanding of the MSC secretome as a therapeutic for treatment of inflammatory or degenerative pathologies focusing on rheumatic diseases. We provide insights on and perspectives for future development of the MSC secretome with respect to the release of extracellular vesicles that would have certain advantages over injection of living MSCs or administration of a single therapeutic factor or a combination of factors.