Over the past decade, the human umbilical cord has been recognized as a significant and ethical source of mesenchymal stem cells (MSCs), particularly Wharton’s jelly (WJ). WJ, as a connective tissue of the cord, possesses gelatinous uniformity and is being studied in regenerative medicine for certain modalities. This mucoid tissue provides a remarkable therapeutic potential through its extracellular matrix components, MSCs, and proteoglycans, while serving biochemical and protective functions during fetal development. This review highlights the advancements in WJ’s biological structure and function, biomechanical characteristics, and regenerative capacities, with a special focus on WJ-acquired MSCs alongside their clinical translation. Current research reveals that WJ-MSCs may be used in clinical settings as a potential source due to their high proliferation capacity, differentiation capabilities, and an immunomodulatory profile, compared to adult-tissue-derived stem cells. These significant properties make this tissue a good candidate for cell-based interventions.

Trauma to the articular cartilage leads to movement restriction. As the articular cartilage has a definitive regeneration capacity owing to its avascular and aneural nature, several therapeutic approaches have been explored. Cong et al elaborated on the strategies and innovations in stem cell-based cartilage regeneration. Its systematic organization - advancing from cartilage structure to stem cell sources, engineering methodologies, preclinical studies, clinical applications, and future prospects - offers researchers a coherent framework for understanding this intricate domain. This review highlights current limitations in cartilage repair, engineering innovations, and major preclinical and clinical trials employing stem cell-centered approaches. Despite its comprehensive coverage, this review does not provide an in-depth focus on certain techniques discussed in this article.

BACKGROUND Tendon stem/progenitor cells (TSPCs) are a novel type of stem cell. TSPCs share common characteristics with stem cells, including their proliferation, pluripotency, and self-renewal abilities. Circular RNA plasmacytoma variant translocation 1 (circ_PVT1) has been reported to inhibit senescence in TSPCs. However, the mechanism by which circ_PVT1 regulates the proliferation and differentiation of TSPCs remains unclear. AIM To explore how circ_PVT1 regulates the proliferation and differentiation of TSPCs. METHODS Mouse TSPCs were isolated from the Achilles tendon of 12 male C57Bl/6 mice at postnatal day 30, and 5 ng/mL of transforming growth factor (TGF)-β1 was used to induce the tenogenic differentiation in TSPCs. Picro-Sirius red staining was used to detect the collagen expression of TSPCs. A Cell Counting Kit-8, Transwell assays, and flow cytometry were used to assess the proliferation, migration, and apoptosis of TSPCs. Biochemical kits were used to determine the levels of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, and ATP. Then, N6-methyladenosine (m6A) dot blot and methylated RNA immunoprecipitation polymerase chain reaction (RIP-PCR) were used to examine the m6A levels. Moreover, RNA pulldown and RIP-PCR were performed to analyze the interaction between WTAP and circ_PVT1. RESULTS TGF-β1 treatment induced tenogenic differentiation of TSPCs. Circ_PVT1 knockdown reversed the increase of tendon-specific protein, cell proliferation, and migration that was induced by TGF-β1 treatment. In addition, circ_PVT1 inhibition promoted oxidative stress and mitochondrial damage in the TGF-β1-induced TSPCs. The m6A modification level of circ_PVT1 was upregulated in the TGF-β1-induced TSPCs. Furthermore, RNA pulldown and RIP-PCR showed that circ_PVT1 interacted with WTAP in TSPCs, and the WTAP-mediated m6A modification of circ_PVT1 regulated the differentiation of TSPCs. CONCLUSION WTAP-mediated m6A modification of circ_PVT1 promotes the proliferation and tenogenic differentiation of TSPCs, thereby indicating a promising therapeutic strategy for tendon repair.

BACKGROUND Anti-aging for the preservation and recovery of physical and brain functions may be a major topic of regenerative medicine in the super-aging society. Stem cells and their secretory active molecules can play a central role of regenerative medicine. AIM To investigate whether extracellular vesicles (EVs) from amniotic membrane stem cells (AMSCs) enhance physical activity, including stamina, and cognitive function in a mouse model of facilitated brain-aging, and to elucidate underlying mechanisms. METHODS EVs were collected from conditioned media of AMSCs after hypoxic (2% O2, 5% CO2) cultivation for 3 days. The size and composition of EVs was analyzed via nanoparticle-tracking analysis and proteome/lipidome profiles, and functional molecules such as growth factors and neurotrophic factors were analyzed via enzyme linked immunosorbent assay. Male ICR mice were subcutaneously administered with D-galactose (300 mg/kg) for 6 weeks to induce facilitated aging, during which intravenously injected with EVs (6 × 108 exosome particles/body) at weeks 0, 2, 4, and 6. Physical activity and cognitive function were assessed through Rota-rod, forced swimming and passive avoidance performances, respectively. To clarify underlying mechanisms, acetylcholine (ACh), brain-derived neurotrophic factor (BDNF), sirtuin 1 (SIRT1), glial fibrillary acid protein (GFAP), glycogen, and thiobarbituric acid-reactive substances (TBARS) were analyzed in the brain and muscles. RESULTS Six-week injection of D-galactose decreased physical activity and impaired learning and memory function, along with the reduced ACh, BDNF, SIRT1, and glycogen in the brain and muscles, whereas brain GFAP and muscular TBARS increased. However, EV treatment recovered the D-galactose-induced neurobehavioral deficits not only by increasing BDNF and SIRT1 (regulating neuro-muscular adaptation and function) and enhancing brain ACh (governing memory acquisition), but also by restoring muscular glycogen (an energy source) and attenuating brain GFAP and muscular TBARS (inflammatory and oxidative injury markers). CONCLUSION EVs from AMSCs restored cognitive function of mice with facilitated brain-aging by increasing ACh, BDNF, and SIRT1. EVs also enhanced stamina not only by attenuating tissue injury, but also by strengthening the muscles through the production of glycogen and BDNF.

Adipose-derived mesenchymal stem cells (ADSCs) have emerged as an important cell source in regenerative medicine because of their accessibility, abundance, multilineage differentiation potential, and paracrine activity. However, ADSCs are not biologically uniform, and their properties are strongly influenced by donor-related factors, anatomical origin of adipose tissue, and technical procedures used for cell isolation, expansion, and characterization. This review summarizes current advances in defining the source-dependent characteristics of ADSCs, with particular emphasis on donor age, metabolic status, adipose depot specificity, isolation methods, culture conditions, and source-related molecular and functional heterogeneity. Evidence from transcriptomic, epigenetic, immunophenotypic, and secretome studies indicates that ADSCs from different sources may differ substantially in proliferation and differentiation capacity, immunomodulatory activity, and therapeutic performance. Major challenges remain in translating these findings into clinical practice, including donor variability, inconsistent manufacturing workflows, lack of standardized potency assays, and insufficient integration of source-stratified strategies into product development. Emerging directions such as single-cell and multi-omics profiling, cell-free secretome-based therapeutics, and source-aware manufacturing frameworks may improve precision and reproducibility in ADSC-based therapies. A clearer understanding of ADSC source dependency will be essential for optimizing donor selection, improving product consistency, and advancing the safe and effective clinical translation of regenerative medicine applications.

Irreversible degeneration of retinal neurons and the retinal pigment epithelium is a major cause of vision loss, and current pharmacological or surgical treatments seldom rebuild lost tissue, placing stem cell-based regeneration at the center of therapeutic exploration. Retinal progenitor cells, Müller glia (MG)-derived progenitors, pluripotent stem cell-derived retinal pigment epithelium and photoreceptors, and emerging human retinal stem cell candidates together provide a diverse cellular repertoire whose behavior is governed by tightly coordinated fate-control mechanisms. Enabled by single-cell and spatial multi-omics in developing human retina and retinal organoids, these mechanisms can now be mapped at unprecedented resolution, revealing how distinct lineage trajectories and molecular states arise. This review synthesizes a multilayered framework of fate regulation encompassing the diversity and plasticity of embryonic progenitors, MG-derived progenitors, ciliary margin-like cells and putative adult retinal stem cells, and examines how transcription factor hierarchies, epigenetic landscapes, and non-coding RNAs interact with translational, metabolic and inflammatory cues to shape competence windows and photoreceptor vs inner retinal fates in development and disease. These insights are then connected to next-generation regenerative strategies, including engineered retinal organoids and sheets, MG reprogramming, and rational combinations of gene and cell therapies designed to precisely steer cell identity, maturation and circuit integration. By framing retinal regeneration within this multilayered control paradigm, we highlight key challenges for clinical translation and outline how targeted manipulation of fate-regulatory networks may accelerate the development of safe and effective stem cell therapies for blinding retinal disorders.

BACKGROUND Poly-L-lactic acid (PLLA) has been demonstrated to grow both subcutaneous adipose tissue and the dermis which may occur through stimulation of adipose-derived stem cells (ADSC). These cells maintain the integumentary system by regulating fibroblasts and immune cells, sustaining the extracellular matrix, and combating oxidative stress. AIM To use multiplex immunofluorescence to characterize macrophage subtypes involved in the PLLA-macrophage-fibroblast encapsulations on previously obtained biopsy tissue and quantify changes in the subcutaneous adipose tissue of hip dells (lateral gluteal cleft) treated with PLLA. The secondary objective was to use immunofluorescence to characterize macrophage polarization in the immune response to PLLA treatment. METHODS Multiplex immunofluorescence was used to characterize the macrophage subtypes involved in the PLLA-macrophage-fibroblast encapsulations on previously obtained biopsies from a previous randomized, placebo-controlled clinical trial. RESULTS Absolute counts of ADSC and fibroblasts increased markedly in PLLA-treated tissues compared to baseline and controls. PLLA-macrophage-fibroblast encapsulations were high in ADSC with intense CD105, CD90, preadipocyte factor 1, proliferating cell nuclear antigen, β-catenin levels. This contrasts sharply with distant tissue, which was near absent in those signals and instead dominated by perilipin 1 consistent with mature adipocytes. Additionally, M2 macrophages predominated over M1 in these encapsulations, consistent with late-stage wound remodeling rather than infection-associated inflammation. CONCLUSION The study represents the first time native ADSC phenotype cells have been expanded in humans in vivo . PLLA has a well-established three-decade safety record as a minimally invasive skin-rejuvenation and volumization agent. This study suggests PLLA promotes a regenerative environment and may expand progenitor populations in vivo .

BACKGROUND Acute mesenteric ischemia (AMI) is associated with high mortality owing to delayed diagnosis and the absence of biomarkers capable of distinguishing disease subtypes or inflammatory burden. Mesenchymal stem cells (MSCs) exosomal circular RNAs (circRNAs) show diagnostic potential in other diseases. AIM To evaluate the utility of MSCs exosomal circRNAs in AMI, particularly for early detection and subtyping. METHODS Peripheral blood-derived MSCs (PBMSCs) from 80 patients with AMI (stratified by etiology: 48 arterial AMI, 32 venous AMI, 36 early reversible, 44 late necrotic) and 125 controls were obtained at initial hospital admission. Exosomal circRNAs were isolated via ultracentrifugation, validated by transmission electron microscopy and nanoparticle tracking analysis, and quantified by quantitative real-time polymerase chain reaction. Plasma intestinal fatty acid binding protein (IFABP), d-lactate, interleukin-6 (IL-6), tumor necrosis factor-α, IFABP, D-lactate, IL-6, and neutrophil-to-lymphocyte ratio were measured. Pearson’s test was used to assess the diagnostic performance of receiver operating characteristic analysis. RESULTS Patients with AMI exhibited significantly elevated PBMSCs exosomal circ-Eya3 (P < 0.001) and reduced circEZH2_005 levels (P < 0.001). Circ-Eya3 correlated positively with IFABP (r = 0.606), D-lactate (r = 0.384), IL-6 (r = 0.551), and neutrophil-to-lymphocyte ratio (r = 0.601) (all P < 0.001), whereas circEZH2_005 showed inverse correlations (r = -0.580 to -0.403; P < 0.001). Critically, circEZH2_005 expression was lower in arterial AMI than in venous AMI (P = 0.003). The combination of circ-Eya3, circEZH2_005, and D-lactate achieved excellent diagnostic accuracy (area under the curve = 0.891). Post-reperfusion, circ-Eya3 increased (P < 0.05), while circEZH2_005 decreased (P < 0.05). CONCLUSION PBMSCs exosomal circ-Eya3 and circEZH2_005 serve as novel biomarkers for AMI, reflecting intestinal injury severity, systemic inflammation, and disease subtype. Their integration with D-lactate enables high-accuracy diagnosis, whereas differential expression across arterial/venous AMI and ischemia stages offers clinical utility for guiding intervention strategies.

BACKGROUND Previous studies have found that umbilical cord mesenchymal stem cells (UCMSCs) have the potential to treat refractory lupus nephritis (LN), but their mechanisms have not been elucidated. One pathological feature of LN is the infiltration of multiple immune cells into renal tissue, forming a local immune microenvironment, which leads to renal pathological damage. AIM To demonstrate the changes in the number and proportion of locally infiltrating immune cells in the kidneys of LN mice after UCMSCs treatment. METHODS We analyzed the number and location of different immune cell subsets infiltrating in renal tissues using immunohistochemistry and multiplex immunofluorescence; and analyzed the number of regulatory T (Treg) cells in the mouse spleen using flow cytometry. Finally, we conducted in vitro co-culture of UCMSCs and peripheral blood mononuclear cells to detect the effects of UCMSCs on the differentiation of T helper 1 (Th1), Th17, and Treg cells. RESULTS In our study, UCMSCs can improve renal function, reduce proteinuria, alleviate renal pathological damage, and inhibit immune cell infiltration into renal tissue. Multiple immunofluorescence staining of renal tissue showed that after treatment with UCMSCs, the number of neutrophils, B cells, T cells, and macrophages decreased, but the proportion of Treg in T cells was upregulated, while the proportion of Th17 decreased. The proportion of M2 cells in macrophages increases, while the proportion of M1 cells decreases. In addition to the change in the proportion of infiltrating immune cells, we also found that infiltrating immune cells mainly gather around renal blood vessels, and there is also immune cell infiltration in the glomerulus and renal interstitium, indicating that immune cells may mainly infiltrate renal tissue through vascular endothelium. We further found that the proportion of Treg cells in the spleen of mice increased after UCMSCs treatment. In vitro experiments, we co-cultured UCMSCs with peripheral blood mononuclear cells and found that UCMSCs have inhibitory effects on Th1 and Th17 differentiation, as well as promoting Treg differentiation. CONCLUSION Our study found that after treatment with UCMSCs, the number and proportion of immune cells infiltrating renal tissue changed. It is suggested that UCMSCs may improve LN by reconstructing the local immune microenvironment of the kidneys.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells extensively studied for their immunomodulatory and regenerative potential. Despite their therapeutic promise, MSC efficacy can be limited by poor survival, reduced homing, and variable immunoregulatory activity in inflammatory microenvironments. To overcome these challenges, priming strategies have been developed to precondition MSCs, enhancing their functional performance. Among these, phytocannabinoids, bioactive compounds derived from Cannabis sativa , have gained attention due to their ability to modulate MSC behavior. Beyond cannabidiol and Δ9-tetrahydrocannabinol, several phytocannabinoids interact with a broad spectrum of receptors, including classical cannabinoid receptors (cannabinoid receptor 1 and cannabinoid receptor 2), G protein-coupled receptor 55, transient receptor potential vanilloid channels, and peroxisome proliferator-activated receptor gamma, influencing intracellular signaling, cytokine expression, migration, viability, and importantly, both MSC priming and lineage differentiation. This mini-review critically examines current in vitro and in vivo evidence on phytocannabinoid-mediated priming and differentiation of MSCs, highlighting their effects on immunomodulation, differentiation, and regenerative potential. Collectively, these findings suggest that phytocannabinoid priming represents a promising approach to enhance MSC therapeutic efficacy, although further studies are required to elucidate receptor-specific mechanisms and optimize priming protocols for clinical translation.