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Human pulp stem cells (PSCs) include dental pulp stem cells (DPSCs) isolated from dental pulp tissues of human extracted permanent teeth and stem cells from human exfoliated deciduous teeth (SHED). Depending on their multipotency and sensitivity to local paracrine activity, DPSCs and SHED exert therapeutic applications at multiple levels beyond the scope of the stomatognathic system. This review is specifically concentrated on PSC‐updated biological characteristics and their promising therapeutic applications in (pre)clinical practice. Biologically, distinguished from conventional mesenchymal stem cell markers in vitro, NG2, Gli1, and Celsr1 have been evidenced as PSC markers in vivo. Both perivascular cells and glial cells account for PSC origin. Therapeutically, endodontic regeneration is where PSCs hold the most promises, attributable of PSCs' robust angiogenic, neurogenic, and odontogenic capabilities. More recently, the interplay between cell homing and liberated growth factors from dentin matrix has endowed a novel approach for pulp‐dentin complex regeneration. In addition, PSC transplantation for extraoral tissue repair and regeneration has achieved immense progress, following their multipotential differentiation and paracrine mechanism. Accordingly, PSC banking is undergoing extensively with the intent of advancing tissue engineering, disease remodeling, and (pre)clinical treatments.

Mesenchymal stem cells (multipotent stromal cells; MSCs) have been under investigation for the treatment of diverse diseases, with many promising outcomes achieved in animal models and clinical trials. The biological activity of MSC therapies has not been fully resolved which is critical to rationalizing their use and developing strategies to enhance treatment efficacy. Different paradigms have been constructed to explain their mechanism of action, including tissue regeneration, trophic/anti‐inflammatory secretion, and immunomodulation. MSCs rarely engraft and differentiate into other cell types after in vivo administration. Furthermore, it is equivocal whether MSCs function via the secretion of many peptide/protein ligands as their therapeutic properties are observed across xenogeneic barriers, which is suggestive of mechanisms involving mediators conserved between species. Oxidative stress is concomitant with cellular injury, inflammation, and dysregulated metabolism which are involved in many pathologies. Growing evidence supports that MSCs exert antioxidant properties in a variety of animal models of disease, which may explain their cytoprotective and anti‐inflammatory properties. In this review, evidence of the antioxidant effects of MSCs in in vivo and in vitro models is explored and potential mechanisms of these effects are discussed. These include direct scavenging of free radicals, promoting endogenous antioxidant defenses, immunomodulation via reactive oxygen species suppression, altering mitochondrial bioenergetics, and donating functional mitochondria to damaged cells. Modulation of the redox environment and oxidative stress by MSCs can mediate their anti‐inflammatory and cytoprotective properties and may offer an explanation to the diversity in disease models treatable by MSCs and how these mechanisms may be conserved between species. MSCs exhibit antioxidant properties directly or indirectly. These antioxidant effects of MSCs associate with their therapeutic benefit in an array of pathologies.

Spinal cord injuries (SCIs) are associated with tremendous physical, social, and financial costs for millions of individuals and families worldwide. Rapid delivery of specialized medical and surgical care has reduced mortality; however, long‐term functional recovery remains limited. Cell‐based therapies represent an exciting neuroprotective and neuroregenerative strategy for SCI. This article summarizes the most promising preclinical and clinical cell approaches to date including transplantation of mesenchymal stem cells, neural stem cells, oligodendrocyte progenitor cells, Schwann cells, and olfactory ensheathing cells, as well as strategies to activate endogenous multipotent cell pools. Throughout, we emphasize the fundamental biology of cell‐based therapies, critical features in the pathophysiology of spinal cord injury, and the strengths and limitations of each approach. We also highlight salient completed and ongoing clinical trials worldwide and the bidirectional translation of their findings. We then provide an overview of key adjunct strategies such as trophic factor support to optimize graft survival and differentiation, engineered biomaterials to provide a support scaffold, electrical fields to stimulate migration, and novel approaches to degrade the glial scar. We also discuss important considerations when initiating a clinical trial for a cell therapy such as the logistics of clinical‐grade cell line scale‐up, cell storage and transportation, and the delivery of cells into humans. We conclude with an outlook on the future of cell‐based treatments for SCI and opportunities for interdisciplinary collaboration in the field.

Three‐dimensional biofabrication using photo‐crosslinkable hydrogel bioscaffolds has the potential to revolutionize the need for transplants and implants in joints, with articular cartilage being an early target tissue. However, to successfully translate these approaches to clinical practice, several barriers must be overcome. In particular, the photo‐crosslinking process may impact on cell viability and DNA integrity, and consequently on chondrogenic differentiation. In this review, we primarily explore the specific sources of cellular cytotoxicity and genotoxicity inherent to the photo‐crosslinking reaction, the methods to analyze cell death, cell metabolism, and DNA damage within the bioscaffolds, and the possible strategies to overcome these detrimental effects. Three‐dimensional biofabrication using photo‐crosslinkable hydrogel bioscaffolds has the potential to revolutionize articular cartilage treatment. The photo‐crosslinking process may impact on cell viability and DNA integrity, and consequently on chondrogenic differentiation. In this review, we explore cellular cytotoxicity and genotoxicity inherent to the photo‐cross‐linking reaction, the methods to analyze them, and the possible strategies to overcome these detrimental effects.

Damage to limbal stem cells as a result of injury or disease can lead to limbal stem cell deficiency (LSCD). This disease is characterized by decreased vision that is often painful and may progress to blindness. Clinical features include inflammation, neovascularization, and persistent cornea epithelial defects. Successful strategies for treatment involve transplantation of grafts harvested from the limbus of the alternate healthy eye, called conjunctival‐limbal autograft (CLAU) and transplantation of limbal cell sheets cultured from limbal biopsies, termed cultured limbal epithelial transplantation (CLET). In 2012, Sangwan and colleagues presented simple limbal epithelial transplantation (SLET), a novel transplantation technique that combines the benefits of CLAU and CLET and avoids the challenges associated with both. In SLET a small biopsy from the limbus of the healthy eye is divided and distributed over human amniotic membrane, which is placed on the affected cornea. Outgrowth occurs from each small explant and a complete corneal epithelium is typically formed within 2 weeks. Advantages of SLET include reduced risk of iatrogenic LSCD occurring in the healthy cornea at harvest; direct transfer circumventing the need for cell culture; and the opportunity to perform biopsy harvest and transplantation in one operation. Success so far using SLET is comparable with CLAU and CLET. Of note, 336 of 404 (83%) operations using SLET resulted in restoration of the corneal epithelium, whereas visual acuity improved in 258 of the 373 (69%) reported cases. This review summarizes the results of 31 studies published on SLET since 2012. Progress, advantages, challenges, and suggestions for future studies are presented. This review examines work reporting simple limbal epithelial transplantation (SLET), an innovative technique that uses minimal limbal tissue from the healthy eye to regenerate the cornea in the limbal deficient diseased eye. SLET has the advantages of requiring only 2 mm × 2 mm of limbal tissue; harvest and transplantation is achieved in a single operation; and cell culture laboratories are unnecessary.

The demand for an efficient therapy for alopecia disease has fueled the hair research field in recent decades. However, despite significant improvements in the knowledge of key processes of hair follicle biology such as genesis and cycling, translation into hair follicle replacement therapies has not occurred. Great expectation has been recently put on hair follicle bioengineering, which is based on the development of fully functional hair follicles with cycling activity from an expanded population of hair‐inductive (trichogenic) cells. Most bioengineering approaches focus on in vitro reconstruction of folliculogenesis by manipulating key regulatory molecular/physical features of hair follicle growth/cycling in vivo. Despite their great potential, no cell‐based product is clinically available for hair regeneration therapy to date. This is mainly due to demanding issues that still hinder the functionality of cultured human hair cells. The present review comprehensively compares emergent strategies using different cell sources and tissue engineering approaches, aiming to successfully achieve a clinical cure for hair loss. The hurdles of these strategies are discussed, as well as the future directions to overcome the obstacles and fulfill the promise of a “hairy” feat. Steps toward human hair follicle regeneration. Cell isolation: cell sources for bioengineering can be follicular (bulge stem cells, dermal papilla, and dermal sheath cells) and non‐follicular (keratinocytes, skin‐derived progenitors, and mesenchymal stem cells). Cell expansion: mesenchymal and epithelial cell sources are cultured in vitro. Bioengineering: cell clustering in 3D instructive hair bulbs. Implantation: bulbs could generate functional hair follicles.

A spaceflight has enormous influence on the health of space voyagers due to the combined effects of microgravity and cosmic radiation. Known effects of microgravity (μg) on cells are changes in differentiation and growth. Considering the commercialization of spaceflight, future space exploration, and long‐term manned flights, research focusing on differentiation and growth of stem cells and cancer cells exposed to real (r‐) and simulated (s‐) μg is of high interest for regenerative medicine and cancer research. In this review, we focus on platforms to study r‐ and s‐μg as well as the impact of μg on cancer stem cells in the field of gastrointestinal cancer, lung cancer, and osteosarcoma. Moreover, we review the current knowledge of different types of stem cells exposed to μg conditions with regard to differentiation and engineering of cartilage, bone, vasculature, heart, skin, and liver constructs. Stem cells exposed to real or simulated microgravity show changes in growth and differentiation. The application of microgravity in cell biology represents a new technology used in the field of cancer research and translational regenerative medicine. It extends the current knowledge in the engineering of organoids, spheroids, or tissues (bone, liver, and heart among others) with and without scaffolds.

Neurological disorders are a massive challenge for modern medicine. Apart from the fact that this group of diseases is the second leading cause of death worldwide, the majority of patients have no access to any possible effective and standardized treatment after being diagnosed, leaving them and their families helpless. This is the reason why such great emphasis is being placed on the development of new, more effective methods to treat neurological patients. Regenerative medicine opens new therapeutic approaches in neurology, including the use of cell‐based therapies. In this review, we focus on summarizing one of the cell sources that can be applied as a multimodal treatment tool to overcome the complex issue of neurodegeneration—mesenchymal stem cells (MSCs). Apart from the highly proven safety of this approach, beneficial effects connected to this type of treatment have been observed. This review presents modes of action of MSCs, explained on the basis of data from vast in vitro and preclinical studies, and we summarize the effects of using these cells in clinical trial settings. Finally, we stress what improvements have already been made to clarify the exact mechanism of MSCs action, and we discuss potential ways to improve the introduction of MSC‐based therapies in clinics. In summary, we propose that more insightful and methodical optimization, by combining careful preparation and administration, can enable use of multimodal MSCs as an effective, tailored cell therapy suited to specific neurological disorders. Schematic overview of the most essential aspects of mesenchymal stem cell (MSC)‐based cell therapies in treatment of nervous system diseases. Created with BioRender.com

Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix‐, myo‐, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix‐, myo‐, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD. PDGFRα+ contractile myofibroblasts, AT2‐suppprting lipofibroblasts, and ECM‐producing matrix fibroblasts are all necessary to build the lung during alveolarization and rebuild the lung after acute or chronic injury. Highly sensitive to cues from the alveolar microenvironment, the PDGFRα+ population undergoes dynamic changes to function in disease or regeneration. We summarize the current knowledge of context‐dependent functional stages of interstitial fibroblasts.

Induced pluripotent stem cells (iPSC)‐based therapies have been hailed as the future of regenerative medicine because of their potential to provide treatment options for most degenerative diseases. A key promise of iPSC‐based therapies is the possibility of an autologous transplant that may engraft better in the longer‐term due to its compatibility with the patient's immune system. Despite over a decade of research, clinical translation of autologous iPSC‐based therapies has been slow—partly due to a lacking pre‐defined regulatory path. Here, we outline regulatory considerations for developing an autologous iPSC‐based product and challenges associated with the clinical manufacturing of autologous iPSCs and their derivatives. These challenges include donor tissue source, reprogramming methods, heterogeneity of differentiated cells, controls for the manufacturing process, and preclinical considerations. A robust manufacturing process with appropriate quality controls and well‐informed, prospectively designed preclinical studies provide a path toward successful approval of autologous iPSC‐based therapies. Regulatory considerations for developing a phase I investigational new drug application for an autologous induced pluripotent stem cells‐based therapy.