Search Results (512)

Advancing age is often accompanied by a gradual decline in musculoskeletal (MSK) health and integrity, making the skeleton not just a structural framework; but a dynamic indicator of biological ageing. Bone tissue undergoes continuous remodelling through tightly regulated interactions among osteocytes, osteoblasts, osteoclasts, progenitor cells or mesenchymal stem/stromal cells (MSCs) and growth factors. With advancing age, this balance shifts toward increased resorption, increased adipose tissue formation, reduced bone formation, and deterioration of bone microarchitecture. This eventually can lead to frailty, increased fracture risk and other age-related diseases (ARDs) due to ageing, cellular senescence and inflammaging. Interestingly, bone-derived changes often precede clinical manifestations of these ARDs, suggesting its potential use as an early biomarker for biological ageing and longevity risks. In our review, we explore the possibility of using the bone as a biomarker for ageing, followed by anti-ageing strategies to encourage bone longevity. We begin by discussing our current knowledge of the bone, the bone marrow (BM), changes in the BM with ageing and current methods of tracking bone ageing; both clinically and experimentally. We then explore studies that investigated the anti-ageing strategies, specifically focused on diet, exercises and lifestyle to shift towards enhanced bone health and longevity. Finally, we discuss the limitations of achieving this, what the future of this field may look like and what methods may be used to translate the idea of bone as a biomarker of ageing, from bench to bed. Full article

Urine-derived stem cells (UDSCs) have emerged as a promising cell source for regenerative medicine due to their non-invasive procurement, high proliferative capacity, and potential relevance to kidney-specific repair. Unlike conventional mesenchymal stem cells (MSCs) obtained from bone marrow or adipose tissue, UDSCs originate from multiple regions of the urinary tract and exhibit a unique biological profile that combines MSC characteristics with features of renal progenitor populations. This review provides a comprehensive overview of the current understanding of UDSC biology, including their origin, isolation strategies, morphology, immunophenotypic characteristics, differentiation potential, and secretory profile. Particular attention is given to the expression of renal lineage-associated markers and pluripotency-related factors that may contribute to their regenerative capacity. The bioactive mediators of UDSCs regulate inflammation, oxidative stress, angiogenesis, and extracellular matrix remodeling, thereby influencing key pathways implicated in chronic kidney disease (CKD)-associated fibrosis. Furthermore, the intrinsic renal progenitor signature of UDSCs may provide advantages in renal homing and tissue-specific repair compared with conventional MSC populations. Despite encouraging preclinical findings, significant challenges remain, including cellular heterogeneity, inconsistent isolation efficiency, lack of standardized characterization criteria, and limited clinical validation. Collectively, current evidence positions UDSCs as a biologically distinct and therapeutically attractive platform for kidney regeneration. Full article

Genitourinary syndrome of menopause (GSM) is a common hypoestrogenic condition marked by vulvovaginal atrophy and lower urinary tract symptoms that significantly impair quality of life in peri- and postmenopausal women. Although local estrogen therapy remains the standard of care, its use is constrained by contraindications, adherence challenges, and concerns regarding long-term safety, particularly in women with estrogen-sensitive conditions. As a result, interest has grown in regenerative, non-hormonal alternatives. Stem cell-based therapy, particularly using mesenchymal stem cells (MSCs), has emerged as a potential therapeutic strategy for restoring urogenital tissue structure and function. The current body of evidence largely consists of preclinical studies, small clinical case series, and investigations in related but distinct conditions, which provide potential mechanistic insights. Preclinical studies suggest that MSCs from adipose tissue, bone marrow, and umbilical cord promote vaginal epithelial regeneration through paracrine mechanisms, including angiogenesis, immunomodulation, extracellular matrix remodeling, and restoration of local estrogen signaling and vaginal microbiota. To date, current clinical studies have not provided direct evidence on the efficacy of characterized MSC-based therapies specifically in GSM populations. Early clinical evidence, primarily involving adipose-derived tissue products such as micro-fragmented adipose tissue, reports improvements in symptoms overlapping with GSM, including vaginal dryness, dyspareunia, urinary symptoms, and sexual function, with benefits lasting up to two to three years after a single treatment and no serious adverse events reported. However, available data are limited by small cohorts, the absence of randomized trials, and regulatory variability. This review summarizes current evidence and outlines key scientific, ethical, and regulatory challenges that must be addressed to guide future research and clarify the therapeutic potential of MSC-based approaches in GSM, ultimately enabling translation. Full article

The nano-hydroxyapatite/β-tricalcium phosphate composite (nano-HA/β-TCP) is widely used in various medical and dental procedures. The absence of in vivo toxicity of nano-HA/β-TCP has been extensively studied, and it is considered one of the most effective synthetic biomaterials for promoting cell differentiation in bone regeneration. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are the primary cell type involved in the osteoinductive process of guided bone regeneration following injury. In the present study, rat BM-MSCs were cultured with nano-HA/β-TCP (80/20%) composite spheroids, and the interaction between the cells and the composite was analyzed using transmission electron microscopy (TEM). Ultrathin sections examined by TEM showed extensive interaction between nano-HA/β-TCP and BM-MSCs. Semi-thin sections stained with toluidine blue revealed the incorporation of the biomaterial into the cell cytoplasm. For the immunohistochemistry analysis, eight adult male Wistar rats weighing approximately 300 g were used in each group. Two bilateral, non-critical-sized 3 mm defects were created in the parietal bones of the calvaria: Control, Bio-Oss^®, and Blue Bone^® (n = 24) during a 12-week experimental period. Bone formation was evaluated through osteonectin and osteopontin expression. At the ultrastructural level, internalization of the biomaterial and close association with the endoplasmic reticulum (ER) and mitochondria were observed. TEM analysis also revealed no harmful effects on the cells, such as apoptotic or necrotic bodies or cell lysis. These findings indicate that the nano-HA/β-TCP composite demonstrates in vitro biocompatibility and interacts appropriately with BM-MSCs, including incorporation into the cell cytoplasm. In vivo, the Blue Bone^® group exhibited superior bone formation when compared with the other groups. Full article

Cardiovascular diseases (CVDs) remain the foremost cause of death globally, responsible for 19.2 million deaths and 437 million disability-adjusted life years in 2023, with prevalent cases having more than doubled since 1990. No approved therapy restores myocardium lost to infarction. The adult heart replaces cardiomyocytes at approximately 1% per year in young adults, declining to about 0.45% per year with ageing, far below what is needed to recover the more than one billion cells destroyed by a large myocardial infarction. Cell-based regenerative strategies have been investigated for more than two decades, encompassing bone marrow mononuclear cells (BM-MNCs), mesenchymal stromal cells (MSCs), cardiac progenitor cells, cardiosphere-derived cells (CDCs), skeletal myoblasts, and induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Safety has been consistent. Efficacy has been modest and variable: the CADUCEUS trial demonstrated scar mass reduction with CDCs without proportionate ejection fraction improvement; the Phase 1/2 POSEIDON trial confirmed MSC safety in 30 patients; and the Phase 3 DREAM-HF trial, enrolling 537 patients, failed its primary endpoint (HR 1.2, p = 0.406). Mechanistic work has established that transplanted cells engraft poorly and exert their benefit principally through paracrine signalling mediated by secreted extracellular vesicles and exosomes carrying microRNAs, trophic factors, and immunomodulatory proteins. For iPSC-CMs, electrophysiological immaturity and arrhythmogenic risk in primate models remain unresolved barriers. Emerging strategies include CRISPR-engineered hypoimmune iPSC lines, bioengineered cardiac patches, injectable hydrogel scaffolds, and engineered exosome platforms. This review provides a comprehensive synthesis of preclinical and clinical evidence, examines translational barriers, and identifies the scientific and regulatory priorities required before these therapies can enter routine clinical practice. Full article

When delivered intravenously, mesenchymal stem cells (MSCs) enhance fracture healing and can be injected at various time points, but the optimal timing remains unclear. This study aimed to clarify the optimal timing of MSC delivery to enhance the healing. For-ty-nine Wistar rats with femoral shaft fractures were randomized according to injection timing: immediately after fracture (group A, n = 14), 24 h after fracture (group B, n = 14), 7 days after fracture (group C, n = 14), and control group (group D, n = 7). Allogeneic bone-marrow-derived MSCs (5.0 × 10⁶ cells) were administered intravenously. Rats were euthanized at 6 weeks post-fracture for analysis. In each group, seven rats were evaluated for new bone formation and histological examination. Another seven rats in group A, B, and C were evaluated for VEGF, TGF-β1, and BMP-2 expression. Group C showed significantly higher new bone formation than groups A, B and D (p = 0.017, p = 0.003, and p = 0.005). Histological grades were higher in group C than in groups D (p = 0.018). In Western blot analysis, VEGF and BMP-2 were higher in group C (p < 0.05). Real-time polymerase chain reaction revealed higher VEGF and TGF-β1 RNA expression in group C (p < 0.05). MSCs administration at 7 days post-fracture is suggested to be the optimal timing for intravenous injection to enhance fracture healing in a rat long bone fracture model. Full article

This in vitro study investigates the effects of therapeutic magnetic resonance (TMR^®), a novel biophysical stimulation technology, on mesenchymal stromal cells (MSCs) to support its potential application in regenerative medicine. The role of pulsed electromagnetic fields in bone healing is already established. We evaluated whether TMR^® influences MSC proliferation, differentiation, and immunomodulatory properties in vitro. Bone marrow-derived MSCs (BM-MSCs) and adipose-derived MSCs (AD-MSCs) were cultured with or without TMR^® exposure and assessed through flow cytometry, karyotype analysis, senescence assays, proliferation tests, gene expression analysis, and osteogenic differentiation assays. TMR^® did not alter MSC phenotype, proliferation, senescence, or genomic stability, confirming its safety profile. Notably, treated MSCs showed enhanced osteogenic differentiation, with increased early expression of key osteogenic markers (RUNX2, ALP, and COL1A1) and greater collagen deposition compared to untreated controls. TMR^® reduced peripheral blood mononuclear cell proliferation and MSC ROS production, suggesting anti-inflammatory and antioxidative effects. Overall, TMR^® appears to be a safe, non-invasive stimulus able to promote osteogenic differentiation, supporting its potential clinical application in bone regeneration. Further in vitro studies and clinical trials are needed to confirm these findings. Full article

Background/Objectives: Modern approaches for post-stroke rehabilitation cover mechanistically different ways—from physiotherapy to digital technologies. Among these approaches, stem cell-based therapy represents probably the most complex but promising strategy. Methods: We discuss the current state-of-the-art of using mesenchymal stem cells (MSCs) in post-stroke regenerative therapy. Despite relatively wide use of bone marrow and adipose tissue MSCs, these cells represent a more mature (“adult”) state, which limits their proliferative and regenerative potentials. Compared to the “adult” MSCs, less “mature” MSCs obtained from umbilical cord, specifically Wharton’s jelly MSCs (WJ-MSCs), demonstrate unique functional capabilities and are free from certain technical and ethical issues. Results: The molecular and cellular mechanisms of action of WJ-MSCs are thoroughly discussed in comparison with abundantly used “adult” types of MSCs. We also comparatively evaluate their preclinical and clinical application for treating post-stroke patients. Recent findings indicate that not only MSCs but also their secretome/exosomes (cell-free product) represent a therapeutically beneficial cellular drug in post-stroke recovery. Specially designed and carefully evaluated protocols, which preserve the bioactivity of the cell-free product intact, are mentioned. Neuroprotective and neuroreparative properties of cell-free products—secretome and exosomes—derived from Wharton’s jelly MSCs are summarized. Conclusions: Cell-free products obtained from WJ-MSCs are an innovative adjunct therapy for post-stroke disorders, despite certain challenges and limitations of this type of therapy still present. By further investigation of the molecular composition and biological mechanisms of the WJ-MSC secretome and exosomes, their clinical applicability in neuroinflammatory and neurodegenerative pathologies will be promoted. Full article

Vascularization remains a fundamental bottleneck in tissue engineering, as the absence of functional vascular networks limits oxygen and nutrient delivery, resulting in necrotic cores and poor host integration. While structural scaffold design and cell sourcing have advanced considerably, emerging evidence indicates that paracrine signaling, rather than direct cell contact or scaffold architecture alone, is the primary driver of angiogenesis and vasculogenesis within engineered constructs. Key cell types, including endothelial cells (ECs) and mesenchymal stem cells (MSCs), engage in bidirectional paracrine crosstalk through the secretion of vascular endothelial growth factor (VEGF), angiopoietins, hepatocyte growth factor, and platelet-derived growth factor, among other mediators. While researchers have long focused on improving scaffold structure and cell selection, growing evidence shows that the chemical messages cells send to one another play a far more important role in driving blood vessel formation than previously appreciated. This review explores how cells embedded within engineered scaffolds communicate through secreted signals to coordinate the growth of new blood vessels. Two cell types, MSCs and ECs, are central to this process: cells that line blood vessels and bone marrow-derived stem cells. These cells exchange a variety of chemical messages that instruct neighboring cells to multiply, move, and organize into vessel-like structures. Importantly, the material properties of the scaffold itself, including its stiffness, surface texture, and degradation over time, influence the signals cells produce and how those signals spread through the tissue. Strategies to amplify paracrine signaling include growth factor-loaded delivery systems, hypoxic and genetic preconditioning of MSCs, and perfusion bioreactor culture. In vitro and in vivo evidence consistently demonstrates that coculture systems leveraging paracrine interactions produce superior vascular outcomes compared to single-cell or acellular constructs. Despite this progress, challenges related to signaling complexity, reproducibility, and clinical translation persist. Integration of transcriptomic and proteomic profiling, computational modeling, and machine learning approaches offers a path toward rationally designed scaffolds that recapitulate the spatiotemporal dynamics of native vascular signaling and ultimately support functional tissue regeneration. Full article

Stage-specific embryonic antigen-3-positive pluripotent-like/macrophage-like multilineage-differentiating stress-enduring (Muse) cells are a distinct subpopulation of mesenchymal stromal cells (MSCs), accounting for 1% to several percent of MSCs. Although stem cell therapy for spinal cord injury (SCI) typically targets the subacute phase to avoid the hostile acute environment, the therapeutic window for Muse cells remains unclear. C57BL/6J mice with severe T9 contusion SCI received a single tail vein injection of human bone marrow-derived (BM) Muse cells, BM-MSCs (both 5 × 10⁴ cells), or vehicle at 2, 8, 14, or 28 days post-injury (DPI) without immunosuppressants. Among the different administration time points, the 2-DPI Muse cell group exhibited significantly higher Basso Mouse Scale scores than the BM-MSC and vehicle groups from 14 days after injection, while no significant differences were observed at the other administration time points. The 2-DPI Muse cell group showed significantly greater homing to the injured spinal cord than the BM-MSC group, with persistent engraftment and neural-lineage marker expression at day 42. Ablation of engrafted Muse cells at day 42 partially reversed locomotor recovery, suggesting that engrafted Muse cells contributed to functional recovery. These findings suggest that intravenous Muse cell therapy exerts timing-dependent therapeutic effects after SCI, with greater efficacy during the early post-injury phase. Full article

The development of reusable and biocompatible biomaterial-based culture substrates is increasingly relevant for improving sustainability in biomedical research workflows. In this study, polyethylene terephthalate glycol-modified (PETG) was evaluated as a potential alternative to conventional polystyrene (PS) for in vitro cell culture applications. PETG substrates were fabricated through laser cutting and tested for their ability to support cell adhesion, viability, proliferation, and lineage-specific differentiation across multiple human cell models, including calvarial mesenchymal stromal cells (CMSCs), bone marrow-derived mesenchymal stromal cells (hBM-MSCs), dermal fibroblasts, LHCN-M2 myoblasts, and SH-SY5Y neuroblastoma cells. Morphological and immunofluorescence analyses demonstrated that PETG supported cell attachment and focal adhesion formation, comparable to standard PS surfaces. Cell viability and proliferation assays confirmed metabolic activity and growth over time. Furthermore, PETG substrates supported osteogenic, adipogenic, myogenic, and neuronal differentiation, as demonstrated by histological staining, myotube formation, neurite outgrowth, and lineage-specific gene expression analyses. Finally, PETG maintained CMSC morphology and metabolic activity after repeated recovery, ethanol/UV treatment, and gelatin re-coating, with comparable results between new substrates and those reused for up to three cycles. These findings support PETG as a biocompatible culture substrate with preliminary short-term reuse potential and possible sustainability benefits for laboratory workflows. Full article

Bone marrow aspirate concentrate (BMAC) is widely used as a source of mesenchymal stromal/stem cells (MSCs) for musculoskeletal regeneration; however, BMAC lacks essential bone marrow extracellular matrix (ECM) components, a critical component of the stem cell niche that regulates MSC survival, paracrine signaling, and regenerative capacity. We previously demonstrated that an ECM-retaining micronized bone marrow product (BMAX™) preserves pro-regenerative MSC phenotypes in vitro. Human bone marrow from a single donor was processed into conventional BMAC or BMAX™. Post-traumatic osteoarthritis was induced in immunodeficient rats using destabilization of the medial meniscus (DMM). Four weeks after surgery, animals were randomly assigned to receive intra-articular injections of BMAX™, BMAC, or phosphate-buffered saline (n = 10–12 in each group). Pain-related behavior (n = 5–6/group), histological assessment (n = 3–6/group), and micro-computed tomography (n = 4–6/group) were evaluated for up to 8 weeks after treatment. At 4 weeks after treatment, BMAC significantly increased the paw withdrawal threshold compared with PBS (p = 0.0068), whereas BMAX™ significantly reduced knee joint swelling compared with both PBS (p = 0.0235) and BMAC (p = 0.0039), and BMAX™ significantly improved knee bend scores compared with PBS (p = 0.0011). Neither treatment significantly improved OARSI histological scores at this time point. At 8 weeks after treatment, BMAX™ significantly increased the paw withdrawal threshold compared with PBS (p = 0.0305), whereas BMAC showed a non-significant trend (p = 0.0517); both treatments significantly reduced knee bend scores compared with PBS (p = 0.0027 and p = 0.0255), and BMAX™ demonstrated significantly lower knee bend scores than BMAC (p = 0.0090). BMAX™ significantly reduced knee swelling compared with PBS (p = 0.0196). Histologically, BMAX™ significantly improved OARSI scores in both the femoral condyle and tibial plateau compared with PBS (p = 0.0020 and p = 0.0003, respectively), whereas BMAC significantly improved only tibial plateau OARSI scores (p = 0.0014). Furthermore, BMAX™ demonstrated significantly lower femoral condyle OARSI scores than BMAC (p = 0.0243). Micro-computed tomography revealed that both BMAX™ and BMAC significantly reduced medial subchondral trabecular separation compared with PBS (p = 0.0340 and p = 0.0426, respectively), whereas no significant differences were observed between the two treatment groups for other bone structural parameters. In conclusion, preservation of the native bone marrow ECM was associated with improved functional outcomes and greater cartilage regeneration compared with conventional BMAC in this preclinical rat model of post-traumatic osteoarthritis. These findings support the concept that maintaining the native stem cell niche may enhance the therapeutic potential of bone marrow-derived cell therapies for osteoarthritis. Full article

Background: Intra-articular (IA) stem cell injection is an emerging treatment for knee osteoarthritis (KOA). Three principal cell sources—adipose-derived mesenchymal stem cells (ADMSCs), bone marrow-derived MSCs (BMMSCs), and peripheral blood-derived stem cells (PBSCs)—have been evaluated independently; however, a systematic review comprehensively comparing all three sources under unified eligibility criteria is absent from the literature. Methods: Systematic searches of MEDLINE, Embase, Cochrane CENTRAL, and Scopus were conducted from inception to December 2025, supplemented by manual reference screening and ClinicalTrials.gov. Eligible studies included randomized controlled trials (RCTs) and prospective comparative studies in adult KOA patients. Primary outcomes were pain (VAS/NRS) and function (WOMAC, KOOS) at ≥3 months. Risk of bias was assessed using RoB 2 and ROBINS-I; evidence certainty was rated using GRADE. Results: Thirty-one studies (n = 1247; ADMSC: 14 studies, n = 612; BMMSC: 12 studies, n = 487; PBSC: 5 studies, n = 148) met inclusion criteria. Pooled standardized mean differences (SMDs) for 6-month pain showed significant reduction versus comparators for ADMSCs (SMD −1.23; 95% CI −1.61 to −0.85; I² = 62%) and BMMSCs (SMD −1.09; 95% CI −1.55 to −0.63; I² = 70%). PBSCs demonstrated significant within-group improvement but were too few for formal pooling. Because no trial compared cell sources head-to-head, these estimates reflect within-source efficacy versus each study’s own comparator rather than comparative superiority between sources. Adverse events were mild and transient across all sources. GRADE certainty was moderate for ADMSCs, low for BMMSCs, and very low for PBSCs. Conclusions: IA injection of ADMSCs and BMMSCs provides pain reduction and functional improvement in KOA with point estimates reaching minimal clinically important difference thresholds, although the certainty of this evidence is only moderate (ADMSC) to low (BMMSC). PBSC evidence is insufficient for formal comparison. Adequately powered, three-arm head-to-head RCTs that share a common comparator and a core outcome set are needed to establish comparative efficacy. Because only indirect comparisons were possible, this review supports efficacy within each cell source but cannot establish the superiority of one source over another. Full article

Critical-sized bone defects lack spontaneous healing capacity. While mesenchymal stem cell-derived exosomes (sEVs) are promising osteoinductive agents, their rapid in vivo clearance limits their free-form efficacy. Here, we fabricated a nano-hydroxyapatite/chitosan (nHA/CTS) composite scaffold as a protective, sustained-delivery platform for human umbilical cord blood-derived mesenchymal stem cell exosomes (HUCB-MSCs-exos) to accelerate bone repair. The 3D porous CTS/10% nHA scaffold exhibited excellent cytocompatibility and a degradation rate commensurate with new bone ingrowth. Critically, it enabled a biphasic exosome release profile—an initial burst followed by a 14-day sustained release (89.73% cumulative release). In vitro, HUCB-MSCs-exos significantly promoted the proliferation, migration, and osteogenic differentiation of bone marrow-derived MSCs, as demonstrated by enhanced alkaline phosphatase activity and matrix mineralization. In a rabbit condylar defect model (5 mm diameter), the CTS/10% nHA-exo scaffold achieved a 57.44 ± 8.42% healing rate at two months, nearly two-fold greater than the scaffold-only group (29.33 ± 6.94%). Histological and immunohistochemical analyses at two months confirmed the formation of mature, well-vascularized trabecular bone, accompanied by robust expression of late-stage osteogenic markers (OCN and OPN). These findings demonstrate that the CTS/10% nHA scaffold synergistically integrates osteoconductive structural guidance with exosome-mediated osteoinductive paracrine signaling, providing a compelling and translatable strategy for critical-sized bone-defect management. Full article

Cutaneous leishmaniasis (CL) is the most common clinical form of leishmaniasis, characterized by persistent skin ulcers and nodules. Standard chemotherapeutic agents have substantial toxicity and do nothing to repair the damaged tissue, an unmet need that motivates the search for adjunctive strategies. Mesenchymal stem cells (MSCs) can modulate macrophage activity and support tissue regeneration, yet their role in CL has received limited attention. In this study, we tested whether bone marrow-derived MSCs (BM-MSCs) could attenuate Leishmania mexicana-induced inflammation and facilitate skin repair. Indirect co-culture of BM-MSCs with infected RAW264.7 macrophages shifted the macrophage phenotype from M1 toward M2, with higher IL-10 and Arg-1 expression and lower iNOS and IL-1β. In BALB/c mice with established CL, three weekly intravenous injections of BM-MSCs reduced paw swelling, improved skin histology, decreased type I collagen deposition, lowered Integrin β1 and Cytokeratin 17 expression, and reduced tissue parasite load. Immunofluorescence confirmed a predominantly M2 macrophage distribution in treated lesions. We inferred that BM-MSCs acted on both the immune and reparative aspects of the disease process, supporting their potential as an adjunct to conventional anti-leishmanial therapy. Full article