Low back pain (LBP) is a leading cause of global disability, with around 40
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies. Not applicable.
Abstract Background Neonatal bronchopulmonary dysplasia (BPD) is a lung injury caused by various factors, including intrauterine inflammation, mechanical ventilation, and oxidative stress. BPD results in serious respiratory and neurological dysfunctions and mortality. Recently, some clinical trials have commenced using intravenous delivery of donor-derived multilineage-differentiating stress enduring (Muse) cells. In the present study, we aimed to investigate the therapeutic effects of human Muse cells in hyperoxia-induced neonatal lung injury in a rat model with features of bronchopulmonary dysplasia. Methods Rats were put into the incubator within 24 h from birth to expose to hyperoxia (83%) until postnatal day 15. Muse and non-Muse cells, obtained from the bone marrow-mesenchymal stromal cells (MSCs) as stage-specific embryonic antigen-3 (SSEA-3)+ and −, respectively, were administered slowly via the right external jugular vein or trachea (Muse cells only) on postnatal day 5. For the vehicle groups, only the acetic acid Ringer's solution was administered. Results Respiratory function, histological findings, and inflammatory parameters did not differ significantly between intravenous and intratracheal administration. In contrast, body weight gain and survival were worse following intratracheal administration. Intravenous administration of Muse cells resulted in superior amelioration of lung tissue injury, inflammation, and pulmonary hypertension compared with non-Muse cells. We also confirmed the engraftment of Muse cells in the lung tissues. Proteomic profiling identified hyperoxia-induced lung injury associated changes in the abundance of proteins annotated to cell adhesion and coagulation/fibrinolysis-related pathways, and Muse cell administration was associated with differential abundance of subsets of these proteins. Conclusions Our findings suggest that intravenously transplanted Muse cells provide functional benefits in hyperoxia-induced lung injury in a rat model with features of bronchopulmonary dysplasia.
Idiopathic pulmonary fibrosis (IPF) is a rare, progressive fibrotic disease primarily characterized by recurrent epithelial injury and fibroblast activation. Recent studies have indicated that the accumulation of abnormal airway basal progenitor cells (ABCs) may significantly contribute to the promotion of fibrosis, serving as a prerequisite for the onset and progression of IPF. However, the underlying mechanisms remain inadequately understood. ABCs form IPF patients and healthy controls were obtained by bronchoscopic brushing and cultured with specific medium. Collecting the cell supernatant, their EVs were isolated by ultracentrifuge. Human lung fibroblasts were treated with EVs to evaluate the effect of activation, proliferation, and migration in vitro. Furthermore, the administration of EVs via inhalation to healthy mice and pulmonary fibrosis model mice was undertaken in order to ascertain the impact on fibrosis progression in vivo. Furthermore, a comprehensive profiling of the microRNA presented within EVs from IPF- and health control-ABCs was conducted. IPF and health ABCs were extracted and identified successfully, with IPF ABCs revealed to promote fibroblast activation. Subsequently, the EVs from IPF and healthy ABCs were isolated and characterized. Our findings indicated that IPF EVs exhibited a predominant role in fibroblast activation, but didn’t contribute to proliferation and migration. However, control-EVs were found to promote fibroblasts proliferation and migration in vitro. Furthermore, we found IPF-EVs induced pulmonary septal thickening and collagen deposition in vivo, while health-EVs suppressed collagen deposition in lung fibrosis induced by bleomycin. Furthermore, the presence of differentially expressed microRNAs in EVs derived from IPF and health ABCs (including has-miR-141-3p, hsa-let-7b-3p, has-let-7f-1-3p, etc.) has been observed. These differentially expressed miRNAs have the potential to enrich in collagen metabolic procession, WNT signaling, and JAK/STAT signaling pathway. These findings suggest that EVs derived from ABCs are associated with fibroblast-related fibrotic responses and may contribute to intercellular communication during IPF progression.
The olfactory ensheathing cell (OEC) secretome includes neurotrophic factors, cytokines, extracellular matrix proteins, and other signaling molecules that influence neuronal behavior including survival, proliferation, and differentiation. However, mechanisms by which the secretome modulates neuronal responses remain unclear. Here, we report a newly identified category of cell secretomes derived from human OECs, termed dehydration-induced secretome (DIS). This approach involves dehydrating OECs, followed by rehydration in phosphate-buffered saline, which induces the extensive formation of membrane vesicles ranging from exosome-sized particles to larger vesicles visible under a microscope. After centrifugation to remove larger vesicles, the supernatant containing both soluble proteins and exosome-sized vesicles was collected and defined as the DIS. We compared the DIS with our previously reported conventional secretome, analyzed protein expression patterns, and assessed functional implications. We also investigated the protective effects against oxidative stress, induction of quiescence, and differentiation promoting effect in neural stem cells (NSCs). Proteomic analysis revealed that both secretomes shared similar Gene Ontology terms, indicating functional overlap. Although more proteins were detected in the DIS, their abundance was generally lower than in the conventional secretome. However, the overall protein yield per cell was significantly higher in the DIS group. Only 36 proteins were shared between the two preparations and were primarily associated with actin filaments and glycolysis. Functionally, both the secretome and DIS promote NSC proliferation and differentiation with distinct molecular responses. DIS showed antioxidant activity primarily by reducing ROS accumulation in NSCs under H₂O₂-induced oxidative stress, which was associated with superoxide dismutase activity. Although both secretome and DIS stimulated NSC proliferation and differentiation, their effects on specific neuronal markers and pathways differed. Notably, DIS significantly promoted axonal branching and reduced the expression of quiescence markers more effectively than the conventional secretome. However, DIS did not enhance the expression of the ribosomal protein subunit 6, which was upregulated in the conventional secretome. Overall, DIS from OECs exhibited beneficial effects similar to those of the conventional secretome while offering a higher yield and reduced processing time. It also enabled potentially better responses of NSCs to oxidative stress and quiescence inhibition, making it a therapeutic candidate for neurological diseases. Not Applicable.
Sarcopenia, characterized by age-related loss of skeletal muscle mass and function, poses a significant challenge to lifelong health and wellbeing. Currently, no effective therapeutic interventions exist. In previous work, we developed specialized muscle progenitor cells (MPCs), termed Givi-MPC, from human induced pluripotent stem cells (hiPSCs). These cells demonstrated robust regenerative capacity in both sarcopenic and dystrophic muscle models. However, the potential of extracellular vesicles (EVs) derived from Givi-MPC to rejuvenate aged muscle stem cells (MuSCs) and their niche remains unexplored. This study investigates the therapeutic efficacy of EVs derived from Givi-MPC in sarcopenia. Givi-MPC were generated from hiPSCs using CHIR990021 and givinostat. EVs were isolated from Givi-MPC or primary human myoblast via size exclusion chromatography and characterized by transmission electron microscopy (TEM), Western blotting, and tandem mass tag (TMT)-based mass spectrometry. Aged C57BL/6J mice (24–25 months old) received intramuscular administration of EVs derived from Givi-MPC, and therapeutic efficacy was assessed through grip strength testing, immunohistochemistry, metabolic profiling, and spatial transcriptomics. To evaluate regenerative capacity, aged MuSCs treated with EVs-Givi-MPC or phosphate-buffered saline (PBS) were subjected to in vitro myogenic differentiation and transplanted into mdx/scid mice following cardiotoxin-induced muscle injury. Proteomic analysis revealed that EVs derived from Givi-MPC were enriched in proteins associated with regeneration, angiogenesis, axonal repair, and cellular homeostasis compared to EVs from primary human myoblasts. Treatment with EVs-Givi-MPC significantly increased muscle mass and strength, reduced muscle degeneration, enhanced angiogenesis and reprogrammed the metabolic landscape of aged muscle. EVs-Givi-MPC treatment enhanced clonal expansion and myogenic differentiation of isolated aged MuSCs. Upon transplantation, MuSCs pretreated with EVs-Givi-MPC generated more dystrophin⁺/Myh3⁺ cells at day 5 and a greater number of dystrophin⁺ fibers at day 30 compared to PBS treated controls. Spatial transcriptomics and immunostaining indicated that Givi-MPC EVs reversed MuSCs senescence and reprogrammed their transcriptomic profile toward self-renewal and differentiation, while restoring niche signaling to a more youthful state. EVs derived from Givi-MPC improve muscle mass, fiber cross-sectional area, and grip strength, effectively rejuvenate aged MuSCs and their microenvironment. These findings support the potential of EV-based therapies as a novel approach for treating sarcopenia.
Medication-related osteonecrosis of the jaw (MRONJ) is one of the potential intractable diseases that has no clear pathophysiology and definitive treatment/prevention strategy. Previously, transplantation of quality- and quantity-controlled peripheral blood mononuclear cells (QQ-PBMNCs) or stromal vascular fraction cells (SVFCs) has been demonstrated to reduce/prevent MRONJ-like lesions in mice. However, because the two cell sources were evaluated in separate studies, differences in their effects on osseous and soft tissue healing could not be determined. This study aimed to compare the effects of QQ-PBMNC and SVFC transplantation on osseous and soft tissue healing after normalization to the corresponding control values in a murine model of MRONJ-like lesions. MRONJ-like lesions were created in combination with drug administration (zoledronate and cyclophosphamide) and tooth extraction of both maxillary first molars in female C57BL6/J mice. Prepared QQ-PBMNCs or SVFCs were systemically transplanted following tooth extraction 3 weeks after the start of drug administration. Euthanasia was carried out 2 weeks after tooth extraction. Wound healing-related parameters were compared between MRONJ-like lesions with and without cell-based therapy. The relative superiority of two cell types was evaluated for each parameter. Both cell populations significantly improved osseous and soft tissue healing of tooth extractions in MRONJ-like lesions. Interestingly, SVFCs had superior transplantation effects on osseous healing, and QQ-PBMNCs had superior effects on soft tissue healing of extraction sockets. Transplantation effects were cell source-dependent, with SVFCs and QQ-PBMNCs showing superior efficacy in promoting osseous healing and soft tissue healing, respectively. The selection of optimal cell source may depend on the predominant clinical features of the lesions.
Three-dimensional (3D) spheroid culture has emerged as a promising approach to enhance the therapeutic potential of multipotent mesenchymal stromal cells (MSCs). However, the metabolic mechanisms underlying the functional performance of spheroid MSCs remained poorly defined. In this study, we provide an integrative metabolic characterization of human adipose tissue-derived MSCs during spheroid formation and culture. Human adipose tissue–derived MSCs were cultured as 3D spheroids and analyzed during formation and 7 days’ culture. Cellular bioenergetics were assessed using Seahorse extracellular flux analysis. Global metabolic changes were characterized by untargeted liquid chromatography–mass spectrometry (LC–MS) based metabolomics and lipidomics. Secretion of growth factors was quantified using a Luminex-based multiplex immunoassay. Lipidomic profiles of MSC spheroids were further compared with released extracellular particles. Spheroid culture induced progressive cellular compaction, reduced cell size, and enhanced secretion of pro-regenerative growth factors. Bioenergetics analysis revealed a marked suppression of both oxidative phosphorylation and glycolysis compared with monolayer cultures, indicating a shift toward a quiescent-like metabolic state. Metabolomic profiling demonstrated reduced intracellular amino acid levels, consistent with decreased demand for protein synthesis. Lipidomic analysis revealed extensive lipid remodeling, characterized by enrichment of diacylglycerols and unsaturated fatty acids alongside a pronounced reduction in structural phospholipids. Comparative lipidomic profiling showed substantial overlap between spheroids and the released large extracellular particles, suggesting particle-mediated lipid export. MSC spheroid formation is accompanied by dynamic metabolic reprogramming involving bioenergetic suppression, altered amino acid utilization, and extensive lipid remodeling. These metabolic adaptations represent a central feature of spheroid MSC biology and provide mechanistic insight into their enhanced therapeutic potential, supporting further optimization of spheroid-based regenerative therapies.
The steroid-refractory acute graft-versus-host disease (SR-aGVHD) after allogeneic hematopoietic stem cell transplantation is a life-threatening inflammatory complication caused by donor T-cell recognition of host antigens. Despite considerable progress in anti-inflammatory drugs, their efficacy is currently estimated to be just 50
Engineering the surface of small extracellular vesicles (sEVs) derived from stem cells is a strategy for displaying proteins, targeting ligands such as peptides or antibodies, or other functional molecules on the vesicle membrane to improve tissue- and cell-specific delivery. These modifications can be achieved through several approaches, including genetic engineering of parental cells, chemical functionalization of membrane lipids or proteins, membrane anchor-based display systems, and therapeutic cargo loading to enhance delivery efficiency to diseased sites. Surface-engineered stem cell-derived sEVs have shown considerable promise for the treatment of cancer, neurological disorders, inflammatory conditions, and tissue injury because they combine the intrinsic biological advantages of stem cell-derived vesicles with improved targeting precision. This review summarizes recent advances in the surface engineering of stem cell-derived sEVs for tissue-targeted drug delivery, with emphasis on genetic, chemical, and anchor-mediated modification strategies, targeting ligands, and controlled release approaches that improve therapeutic specificity and efficacy. The review also discusses emerging translational opportunities and current challenges related to the clinical application of surface-engineered stem cell-derived sEVs.
Stem cell-derived extracellular vesicles (EVs) show considerable potential for regenerative medicine. However, their translation is limited by variability in production, cargo composition, and function. Conventional culture conditions influence EV yield and biomolecular composition, but recent studies demonstrate that mechanical cues and biophysical forces during stem cell culture are also critical regulators of EV biogenesis and cargo loading. Here, we review advances in understanding stem cell mechanosensitivity and how modulation of three-dimensional (3D) microenvironments such as matrix stiffness and viscoelasticity, as well as the application of mechanical forces can influence EV production and functional potential, while also discussing potential underlying mechanisms. The aim of this review is to define key parameters for advancing control of EV modulation through mechanical cues which could extensively enhance their potential as therapeutic tools.
Airway basal stem cells (ABSCs), as tissue-resident adult stem cells within the pulmonary epithelium, possess potent self-renewal and multilineage differentiation capacities. They not only serve as the cornerstone for maintaining airway epithelial homeostasis and mediating injury repair, but their dysfunction also acts as a critical factor driving the initiation and progression of chronic respiratory diseases (CRDs). The global incidence of CRDs continues to rise each year, whereas their clinical diagnosis and treatment remain limited by significant bottlenecks. Therefore, in-depth exploration of the biological characteristics and pathological alterations of ABSCs is of great significance for overcoming these clinical dilemmas. This review systematically elaborates on the biological features and fate regulatory mechanisms of ABSCs, and further elucidates the molecular mechanisms underlying the pathological alterations of ABSCs in multiple CRDs. In addition, we summarize the translational prospects of ABSCs in disease modeling, precision medicine, and cell-based transplantation therapy. While recent studies have yielded substantial progress in ABSCs’ basic research, multiple critical barriers still impede their clinical translation. These major obstacles include poorly defined cellular heterogeneity landscapes, intricate intercellular crosstalk within diseased airway niches, and the absence of robust, scalable systems for clinical-grade ABSCs preparation. Resolving these key research gaps is essential to bridge the translational divide between bench research and clinical application. Promoting the clinical translation of ABSCs for CRDs is of great significance. ABSCs can not only play a key role in the early diagnosis and prevention of CRDs, but also hold the potential to transform therapeutic paradigms from symptomatic relief toward fundamental epithelial repair, thereby providing innovative diagnostic and therapeutic strategies for CRDs and other chronic diseases associated with epithelial dysfunction.
Recently, mesenchymal stem cells (MSCs) therapy has emerged as a revolutionary breakthrough in the treatment of T1DM. Nevertheless, its therapeutic efficacy is controversial due to the influence of diverse micro-environment including vitamin D (VD) deficiency. Moreover, it still remains unclear whether VD intervention could enhance the protective effects of MSCs via related pathways. Herein, the purpose of our study was to evaluate the roles of VD in augmenting the protective effects of MSCs on the pancreatic injury by affecting the inflammation, oxidative stress and mitophagy through both in vivo and in vitro experiments. Three-week-old male C57BL/6J mice were respectively fed with different VD diets for 3 weeks. Subsequently, a T1DM mouse model was established through intraperitoneal injection of streptozotocin (STZ) and then treated with MSCs via the tail vein. Then, their metabolic parameters, pancreatic histology, and indicators of oxidative stress and inflammation, as well as mRNA and protein expressions of related genes were analyzed in the serum, pancreatic and/or spleen tissues. Moreover, the roles of VD on the inflammation, oxidative stress, apoptosis, cellular and mitochondrial reactive oxygen species (ROS), and mitophagy were explored using the mouse islet β-cells (MIN-6) in vitro, which was then accurately verified by inhibiting the mitophagy as the Chloroquine (CQ). Herein, among the STZ-induced T1DM mice, VD interventions could effectively enhance the protective effects of MSCs on the insulin secretion and glucose metabolism in the VD+MSCs+T1DM group, as was evidenced by a significantly improved pancreatic β-cell structure, lower concentrations of serum glucose and higher glucose reserve capacity (P < 0.05). Simultaneously, it could alleviate the pancreatic injury, as manifested by higher expressions of Bcl-2/Bax and lower levels of Caspase 3 than those in the T1DM, VD+T1DM and/or MSCs+T1DM groups (P < 0.05). Moreover, comparing with the aforementioned three groups, VD+MSCs+T1DM group exhibited lower expressions of TNF-α, Foxp3, IL17A, cd68, Mcp1 and higher levels of Beclin-1, Pink1, Parkin in the pancreatic tissues, as well as higher contents of serum GSH, CAT, SOD and lower MDA (P < 0.05). Furthermore, comparing with the HG, VD + HG and/or MSCs + HG groups in vitro, VD + HG+MSCs interventions could ameliorate the percents of HG-induced cellular apoptosis, with lower expressions of Bax, Caspase 3 and TOMM20, and higher levels of genes related to VD metabolism such as CYP27A1, CYP24A1 and VDR (P < 0.05). Meanwhile, it could also reduce the contents of cellular and mitochondrial ROS with higher contents of SOD, CAT, GSH, GSH/GSSG and lower levels of MDA (P < 0.05). It was accompanied by the enhanced mitophagy, as indicated by higher expressions of Pink1 and Parkin, which could be partly diminished by inhibiting the mitophagy with CQ (P < 0.05). In sum, appropriate VD intervention both in vivo and vitro could ameliorate the inflammation, oxidative stress and mitophagy to enhance the protective effects of MSCs, suggesting that the clinicians ought to meticulously monitor the VD concentrations among the T1DM patients prior to contemplating the utilization of MSCs as a potential therapeutic approach in the future.
Microtia and related auricular malformations remain among the most challenging problems in reconstructive surgery. Current approaches, including costal cartilage harvesting and auricular chondrocyte progenitor expansion, are constrained by invasiveness, donor-site morbidity, and prolonged culture times. This study aimed to establish a minimally invasive, xeno-free strategy for isolating and expanding mesenchymal stem cells (MSC) from auricular elastic cartilage (MSC-EC) in healthy adults. A tailored mini-biopsy technique was designed to obtain auricular elastic cartilage. Tissue fragments were semi-digested and cultured in StemMACS™ MSC Xeno-free medium, enabling massive cell expansion. Immunophenotypic profiling and CFSE proliferative assays were performed by flow cytometry. Multipotent differentiation into chondrogenic, osteogenic, and adipogenic lineages was assessed in 2D and their capacity to regenerate bona fide elastic-cartilage was evaluated in 3D micro-masses, using histological, cytochemical, immunofluorescence staining and light-sheet fluorescence microscopy. MSC-EC exhibited a canonical mesenchymal phenotype, uniformly expressing HLA-ABC, CD73, CD90, CD105 and CD13, whilst remaining completely devoid of hematopoietic and endothelial lineages (CD45, CD31, CD34, HLA-DRA and CD14), thereby strictly satisfying the International Society for Cell Gene Therapy (ISCT) criteria. Functionally, CFSE kinetics revealed a high proliferative capacity, paired with robust tri-lineage differentiation potential. Crucially, when transitioned into 3D micro-mass cultures, MSC-EC demonstrated a structurally superior chondrogenic capacity compared to bone marrow-derived MSC. Rather than forming unorganised cellular aggregates, MSC-EC autonomously orchestrated the developmental histogenesis of bona fide elastic cartilage. This mimetic morphology was reached by the precise architectural assembly of a functional extracellular matrix meshwork rich in collagen-II, sulphated glycosaminoglycans and peripheral elastin, seamlessly generating classical lacunae arrangements and chondrons. These biomimetic constructs established a highly organised spatial compartmentalisation. Adult auricular elastic cartilage obtained through our surgical method is a clinically accessible and well-tolerated source of bona fide MSC. The robust proliferative and differentiation capacities of MSC-EC underscore their translational promise for auricular reconstruction and wider osteo- and articular regenerative applications. This study was reviewed and approved (approval number CIE/1719/10/2024) on 21 December 2024.
Liver failure (LF) represents a severe clinical syndrome associated with rapid deterioration of hepatic function, high mortality, and limited therapeutic options. Despite extensive research efforts, the complex pathogenesis of LF remains incompletely understood, and effective therapeutic strategies remain limited. Animal models have therefore become indispensable platforms for elucidating disease mechanisms, dissecting pathological processes, and evaluating potential therapeutic interventions. In this review, we systematically summarize major animal models for liver failure research, covering surgical, toxin-induced, drug-induced, metabolic, immune-mediated, ethanol-associated, and gene-editing approaches. We discuss their mechanisms, modeling strategies, advantages, limitations, and translational relevance, with emphasis on their ability to recapitulate key pathological features of human LF. We also discuss recent therapeutic advances assessed in LF models and highlight future perspectives. Finally, we discuss current challenges and future directions, including humanized models, organoid-based platforms, multi-omics integration, artificial intelligence-assisted optimization, and standardized evaluation systems. By integrating current advances and unresolved challenges, this review underscores the importance of refining LF animal models to enhance mechanistic investigations and improve the clinical translation of emerging therapies.
The anatomical separation of bone marrow and thymus limits the efficient generation of human immune cells in vitro and constrains experimental platforms for modeling integrated hematopoiesis. We investigated whether a synthetic human bone marrow could be engineered to support both hematopoietic and T-lineage-associated functions. We generated human induced pluripotent stem cell-derived bone marrow organoids (iBMOs) that self-organize into stromal, vascular, and hematopoietic compartments and provide microenvironmental cues supportive of T cell differentiation. iBMOs produced hematopoietic progenitors and yielded stable stromal stem cell lines (iBOSS) that expressed Notch-associated molecules and supported the differentiation of iPSC-derived hematopoietic progenitors toward T-lineage and dendritic cell-associated populations in vitro. Following transplantation into immunodeficient mice, iBMOs sustained human erythropoiesis and underwent bone formation, demonstrating autonomous niche activity in vivo. This integrated bone marrow organoid platform provides a physiologically relevant system for studying human hematopoietic development and immune cell differentiation and offers a scalable foundation for regenerative medicine and immunotherapy applications.
Age-related skin and hair deterioration causes significant psychosocial morbidity, yet current therapies lack consistent efficacy. Mesenchymal stem cells (MSCs) and their extracellular vesicle (EV)-based therapies are promising regenerative strategies, but their clinical utility remains unclear. We performed a scoping review to evaluate the therapeutic mechanisms and clinical efficacy of MSCs and their EV-related therapies in skin and hair rejuvenation and to identify evidence gaps. A literature screening of MEDLINE, Embase, and the Cochrane Library was conducted. We included preclinical and clinical studies that evaluated MSCs or MSC-derived EV-based products for treating age-related skin deterioration or hair loss. From 1,050 articles screened, 146 studies met the inclusion criteria. For skin rejuvenation, clinical evidence shows that MSCs and their EV-based therapies, particularly when combined with delivery-enhancing modalities like microneedling or fractional laser, may benefit wrinkle indices, skin elasticity, hydration, and pigmentation. For hair regeneration, administration of MSCs and EV-based products was reported to increase hair count and density, with high patient satisfaction and minimal adverse effects. Mechanistically, the data indicate the paracrine effect. Secreted growth factors (e.g., VEGF, HGF, IGF-1) modulate key signaling pathways. In skin, this involves activating the Wnt/β-catenin and TGF-β/Smad pathways to enhance collagen synthesis. In hair, regeneration is promoted through the activation of the Wnt/β-catenin and Akt/ERK pathways. While MSCs and their EVs-based therapies suggest potential therapeutic promise, especially when administered using delivery-enhancing modalities that create microtrauma (such as microneedling, derma-rollers, or fractional lasers), the clinical evidence base is constrained by heterogeneous study designs and a lack of standardization in cell/EV manufacturing and administration. This inconsistency confounds the interpretation of true efficacy. To realize the potential of MSC-based regenerative medicine, future research must prioritize the development of standardized protocols, the execution of robust, large-scale controlled trials, and the establishment of clear efficacy metrics for both skin and hair rejuvenation.
Mesenchymal stromal cells (MSCs) are promising therapeutic candidates for neurodegenerative diseases, including Alzheimer’s disease (AD). However, their limited survival and functionality in pathological environments hinder their therapeutic efficacy. The primary objective of this study was to evaluate the therapeutic efficacy of ethionamide (ETH)-preconditioned MSCs (ETH-MSCs) in mitigating AD pathology. Wharton’s jelly-derived MSCs (WJ-MSCs) were preconditioned with ethionamide, and their therapeutic efficacy was evaluated in both in vitro and in vivo AD models. In vitro, ETH-MSCs were assessed for their ability to modulate microglial inflammation and promote amyloid-β (Aβ) clearance under AD-like conditions. For in vivo studies, ETH-MSCs were injected into the lateral ventricles of 5xFAD transgenic mice. The effects of ETH-MSC administration on glial activation (GFAP and Iba1 expression) and Aβ deposition were evaluated. In vitro, ETH-MSCs reduced pro-inflammatory cytokine secretion by microglia and enhanced Aβ clearance in neurons. In vivo, ETH-MSCs treatment significantly decreased GFAP and Iba1 expression, indicating reduced astroglial and microglial activation, and reduced amyloid plaque burden in 5xFAD mice. Repeated ETH-MSCs injections further boosted Aβ clearance, demonstrating a cumulative therapeutic benefit. Ethionamide preconditioning significantly enhances the neuroprotective and amyloid-clearing capabilities of WJ-MSCs. These findings suggest the potential of ETH-MSCs as an effective therapeutic strategy for AD, with superior efficacy compared to naïve MSCs in both in vitro and in vivo models.
Pediatric disorders consist of genetic, hematologic, neurologic, autoimmune, and inflammatory diseases. These conditions impose long-term health challenges on children, despite many advancements with conventional medicine. Although conventional treatments increase life expectancy and provide better disease control, many present challenges such as toxicity, insufficient control of the disease, and adverse effects on normal growth, development, and quality of life. Many researchers have shown increased interest in using stem cell therapies as an alternative to current medications to allow for complete, sustainable repair of damaged tissues and modification of disease processes (i.e., using stem cells to regenerate tissue or change the way in which a disease occurs). This paper will provide the current information on stem cells used in the treatment of children and the many different types of stem cells, including: hematopoietic stem cells (and their derivatives), mesenchymal stem cells (and their derivatives), induced pluripotent stem cells, embryonic stem cells, tissue-specific progenitor cells, extracellular vesicles, and bioengineered products. This paper will also discuss what is known about the stem cells listed as well as their methods of action, where they might currently be better utilized, and future uses of these cells in children for a variety of types of pediatric diseases. Because each stem cell type listed has very different scientific background and clinical evidence, there is much variability in the amount of scientific evidence available to support stem cell therapies. For example, hematopoietic stem cell transplantation (HSCT) has over 50 years of clinical experience; thus, there are many studies defining the clinical efficacy and long-term outcomes associated with HSCT. Conversely, while there are many published studies supporting the use of mesenchymal stem cells (MSCs), extracellular vesicles (EVs), gene-edited cells, organoids, and many induced pluripotent stem cell-derived therapies, more evidence (clinical and basic science) is still needed to fully establish efficacy for the use of these various stem cells in children with pediatric diseases. In addition to needing more clinical evidence, stem cell-based therapies face many important challenges to the advancement of these therapies, including (but not limited to) long-term safety assessments, manufacturing standardization, regulatory oversight, ethical concerns, and equitable access to advanced therapies. Addressing these challenges will be important for future advances in the use of regenerative medicine in pediatric patients which will also require the rigorous evaluation of new stem cell therapies, the continued improvement of translational mechanisms, and the ongoing incorporation of new techniques (e.g., genome editing, organoid modeling, EV therapeutics, bioengineering, and artificial intelligence) to advance regenerative medicine and demonstrate its value through safe and reproducible clinical trial results.
Mesenchymal stem cell therapy shows promise for ConA-induced acute T cell-mediated hepatitis, yet its therapeutic effect remains far from satisfactory due to limited hepatic homing and poorly defined molecular mechanisms. The aim of this study is to investigate whether hepatocyte growth factor (HGF) modification can enhance the therapeutic efficacy of dental pulp stem cells (DPSCs) and elucidate the underlying molecular targets. We generated HGF-overexpressing DPSCs and evaluated their therapeutic effects on ConA-induced acute T cell-mediated hepatitis in mice. Integrated transcriptomic and proteomic profiling identified molecular targets, which were validated through immunofluorescence and western blotting. A possible HGF-Serpine1 association was examined by molecular docking and co-immunoprecipitation, and Serpine1 concentration was measured with or without c-Met blockade. Loss-of-function experiments were performed by knocking down the expression of HGF in DPSCs and by generating liver-targeted Serpine1-knockdown mice using AAV8-TBG-siSerpine1 to assess in vivo functional dependence. HGF-modified DPSCs (DPSC-HGF) alleviated hepatic injury and inflammation with more liver-specific homing than unmodified cells. Integrated transcriptomic-proteomic analysis revealed Serpine1 as one of the most consistently regulated molecules across ConA model and treatment groups. Serpine1 knockdown reduced inflammatory cytokine expression, whereas exogenous Serpine1 aggravated but did not initiate ConA-induced injury, indicating its role as a disease-responsive amplifier of inflammation rather than an independent initiator. Molecular studies supported a possible HGF–Serpine1 association. Functional studies supported the importance of this axis: HGF knockdown in DPSCs abolished most of the therapeutic efficacy, and liver-specific Serpine1 knockdown using AAV8-TBG-siSerpine1 markedly attenuated the additional anti-inflammatory benefit of DPSC-HGF, indicating that hepatic Serpine1 is one of major mediators of DPSC-HGF’s therapeutic action. In NCTC1469 cells, DPSC-HGF CM treatment lowered Serpine1 levels, while this difference was not observed after anti-c-MET antibody pre-treated, a pattern consistent with possible c-Met involvement. This study identifies Serpine1 as an important pathogenic amplifier in ConA-induced hepatitis and demonstrates that HGF modification enhances the therapeutic effects of DPSCs, with improved hepatic homing and reduced hepatic Serpine1 expression observed as parallel findings. The findings support further evaluation of HGF-modified DPSCs in ConA-induced acute T cell-mediated hepatitis.
