Osteoarthritis (OA) remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking. Accumulating evidence positions mitochondrial dysfunction and impaired mitochondrial quality control as central drivers of chondrocyte failure, extracellular matrix breakdown, and inflammation amplification. Mitophagy—particularly the phosphatase and tensin homolog-induced kinase 1 (PINK1)/Parkin axis—has therefore emerged as an attractive, mechanistically grounded intervention point. In this context, synovial mesenchymal stem cell-derived exosomes (SMSC-Exos) represent a compelling cell-free platform capable of delivering functional biomolecules into inflamed cartilage microenvironments. Recent experimental work demonstrates that engineering SMSC-Exos to deliver the mitochondrial co-chaperone GrpE-like 1 (GRPEL1) restores chondrocyte proliferative and migratory capacity under interleukin-1β stress, preserves anabolic extracellular matrix markers (collagen type II alpha 1/aggrecan), suppresses catabolic mediators (matrix metalloproteinase 13/A disintegrin and metalloproteinase with thrombospondin motifs 5), and mitigates oxidative damage while enhancing mitophagy signatures. Mechanistically, GRPEL1 directly associates with PINK1, and PINK1 knockdown attenuates the protective phenotype, supporting a GRPEL1-PINK1 coupling model. In vivo , intra-articular administration of GRPEL1-enriched SMSC-Exos improves histological cartilage integrity and mitophagy-related readouts in a rat OA model. Here, we synthesize mechanistic implications, highlight interpretive nuances (e.g. , mitophagy activation concurrent with membrane potential recovery), and outline translational priorities, including cargo quantification, mitophagy flux validation, dosing/retention kinetics, manufacturing standardization, and biomarker-driven patient stratification.
Adipose tissue-derived stromal vascular fraction (SVF) is a valuable source of regenerative cells for various clinical applications. However, obtaining a sufficient number of cells from patients with limited adipose reserves, particularly from the pediatric population, is a challenge. A study investigated a two-step enzymatic digestion approach to maximize stem cell yield from small adipose tissue samples. Their work demonstrated that the second collagenase digestion of the residual adipose tissue (typically discarded after conventional isolation) yielded a considerable additional population of viable regenerative cells (SVF2). Although SVF1 contained higher absolute cell numbers, SVF2 exhibited superior plating efficiency and higher colony-forming units per 1000 mononucleated cells. This simple modification substantially improved the regenerative cell yield from limited adipose tissue sources. This review offers a critical evaluation of the study methodology and propose future directions, including the integration of artificial intelligence to optimize digestion parameters, and the establishment of standardized potency assays to facilitate its translation into broader clinical practice.
Allergic rhinitis (AR) is a prevalent chronic inflammatory disease worldwide, characterized by Th1/Th2 immune imbalance, nasal mucosal barrier disruption, and complex interactions among various immune cells. Current pharmacological therapies are primarily symptomatic, often failing to correct underlying immune dysregulation and presenting limitations for long-term use. In recent years, extracellular vesicles (EVs), as key mediators of intercellular communication, have demonstrated significant potential in the immune regulation, diagnosis, and treatment of AR. This review systematically highlights the dual role of EVs in AR pathogenesis. On one hand, immune cell-derived EVs can exacerbate Th2-driven immune responses and inflammatory progression by transporting bioactive molecules, such as microRNAs. On the other hand, mesenchymal stem cell-derived EVs demonstrate potent immunomodulatory and tissue-repair capabilities, regulating the activity of dendritic cells, T cells, B cells, and other immune components, restoring Th1/Th2 balance, and repairing the nasal epithelial barrier through the delivery of molecules such as miR-143. Moreover, EVs, along with their associated proteins, microRNAs, and microbiome-derived information, hold promise as biomarkers for AR diagnosis, subtyping, and therapeutic efficacy prediction. Regarding treatment strategies, mesenchymal stem cell-derived EVs can enhance therapeutic outcomes via diverse administration routes and sustained-release hydrogel systems, and may also serve as carriers for antigens or drugs in combination with immunotherapy. Despite their potential, the clinical translation of EVs is confronted with many challenges, e.g., standardization of isolation methods, large-scale production, targeted delivery, and long-term safety. Future research should focus on engineering EVs, elucidating multi-omics mechanisms, and conducting rigorous clinical validation to facilitate their application in clinical practice.
Tendinopathy is a chronic and degenerative tendon disorder with limited therapeutic options. Recent insights into the cellular pathogenesis of tendinopathy have revealed that tendon-derived stem cells may aberrantly differentiate into chondrocytes under micro-injury-induced endoplasmic reticulum stress. In a recent study published by Tu et al in the World Journal of Stem Cells , thymoquinone - a bioactive compound from Nigella sativa - was demonstrated to inhibit the chondrogenic differentiation of tendon-derived stem cells both in vitro and in vivo , primarily through attenuation of the protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic initiation factor 2/activating transcription factor 4/CCAAT/enhancer-binding protein homologous protein pathway. This article evaluates the significance of these findings within the broader field of tendon biology, highlights methodological strengths, and discusses future research directions for translating thymoquinone into a potential therapy for tendinopathy.
Hematopoietic stem cells (HSCs) occupy the apex of the blood cell hierarchy, and artificial intelligence (AI) is fundamentally reshaping how their biology is decoded from normal self-renewal to malignant transformation and clinical transplantation. Trajectory inference algorithms applied to single-cell multi-omics have resolved continuous HSC differentiation with lineage priming detectable at the single-cell level, while convolutional neural networks trained on chromatin imaging predict HSC biological age and detect epigenetic rejuvenation signatures. In leukemic stem cell (LSC) biology, multi-omics deep learning models map treatment-resistant quiescent LSC subclones, detect minimal residual disease with an area under the curve of 0.97 and predict venetoclax sensitivity in LSC-enriched niches. Deep learning also maps myeloma stem cell niche interactions and spatial heterogeneity in bone marrow biopsies. Virtual screening powered by AI speeds up LSC-targeted drug discovery, and reinforcement learning and digital twin models improve ex vivo HSC manufacturing and industrial-scale production of chimeric antigen receptor-T cells. In transplantation, natural language processing extraction and hybrid models classify risk for graft-vs -host disease into clinically relevant subgroups. Overall, top-performing AI models serve as computational surrogates for stemness biology but challenges in dataset diversity, interpretability and regulatory compliance need to be addressed before being used in a clinical setting.
Currently, mesenchymal stem cells (MSCs) and MSC-based transplantation are used to improve health conditions and increase life expectancy. These therapies are based on the principle that the decline of cell populations is the main cause of reduced regenerative potential and aging. However, metabolic cycle disorders could result from several mechanisms of intercellular communication and cell senescence transmission, independent of special phenotype development. MSCs are sensitive to external influences; therefore, the accumulation of changes in the surrounding tissues, rather than in the cells themselves, contributes to accelerated aging through several biophysical mechanisms. These systemic physiological mechanisms could partially explain such effects, such as the systemic role of MSCs as drivers of inflammaging, an effect that increases with age. These findings have prompted a reevaluation of the potential of MSC subpopulations as novel, unconventional therapeutic targets.
BACKGROUND Preeclampsia (PE) is a serious complication in pregnancy. It is one of the primary causes of maternal and perinatal mortality. Human amniotic epithelial cells (hAECs) and mesenchymal stem cells (MSCs) derived from human umbilical cord blood (hucbMSCs) are both perinatal stem cells, capable of expressing characteristic stem cell surface markers. MSC-derived exosomes (MSCs-exos) exhibit functional properties comparable to those of MSCs, while offering advantages such as greater biological stability and the ability to circumvent potential complications associated with MSC-based therapy. This study utilized hAEC-derived exosomes (hAECs-exos) and hucbMSC-derived exosomes (hucbMSCs-exos) to treat preeclamptic rats and investigate their therapeutic effects. AIM To investigate the therapeutic effects of hAECs-exos and hucbMSCs-exos on PE in rats. METHODS Thirty-two pregnant rats were divided into four groups (normal pregnancy, PE, and two exosome-treated groups; n = 8). The PE model was induced by L-arginine methyl ester. From gestation day 12, the treatment groups received hAECs-exos or hucbMSCs-exos for 7 days, while controls received normal saline. Blood pressure, urinary protein, fetal/placental weight, and tissue analyses were performed. Quantitative data are expressed as the mean +/- SD. Differences among multiple groups were analyzed by one-way analysis of variance (ANOVA), followed by the LSD-t test for pairwise comparisons. A P value < 0.05 was considered statistically significant. RESULTS Compared to the normal pregnancy group, rats in the PE group exhibited significantly elevated blood pressure and 24-hour urinary protein levels, indicating successful model establishment. Furthermore, the PE group showed significantly increased levels of interleukin-6, tumor necrosis factor-alpha, soluble fms-like tyrosine kinase-1, and malondialdehyde, along with decreased fetal/placental weight, levels of interleukin-10, placental growth factor, vascular endothelial growth factor, superoxide dismutase, and placental CD31 expression (P < 0.05). Treatment with both exosomes significantly reversed all these alterations compared to the PE group (P < 0.05). Histological analysis further confirmed that the treatments markedly alleviated renal and placental pathological damage induced by PE. CONCLUSION This study demonstrates that both hAECs-exos and hucbMSCs-exos have therapeutic effects in rats with PE, potentially through mechanisms involving the inhibition of oxidative stress and inflammatory responses.
Advanced therapy medicinal products (ATMPs), encompassing therapies derived from mesenchymal stem cells, induced pluripotent stem cells, and their extracellular vesicles, hold substantial transformative potential for clinical applications. However, their translation from bench to bedside and eventual commercialization is hindered by considerable scientific, manufacturing, and regulatory challenges. This review examines these challenges using a structured framework that synthesizes evidence from recent studies, international guidance documents, and regulatory agency reports. We provide an overview of the global regulatory environment and harmonization efforts that influence ATMP oversight, highlighting the frameworks established by major agencies and international initiatives. Technical discussions cover cell sourcing, scalable bioprocess engineering - including bioreactors, closed system technologies, and tangential flow filtration - product quality attributes, and real-time in-process monitoring, incorporating emerging artificial intelligence-driven process analytical technologies. Special focus is given to advanced considerations such as induced pluripotent stem cells tumorigenicity, emphasizing the risks posed by residual undifferentiated cells and the importance of sensitive assays and genetic integrity evaluation; mesenchymal stem cell-derived exosome production, with attention to scale-up strategies, isolation techniques, and quality control standards; global harmonization of good manufacturing practice and ATMP standards; and artificial intelligence-enabled process analytics for automated, closed-cell culture systems. The review further explores potency assays, product comparability, supply chain logistics, and forward-looking trends, including point-of-care manufacturing and digital twin approaches, aiming to equip researchers, developers, and regulators with strategies to advance ATMP development safely and efficiently, ensuring robust therapeutic efficacy and patient safety for next-generation cell and exosome therapies.
Discarded biological tissues increasingly reveal unexpected value as regenerative reservoirs, particularly as sources of mesenchymal stem cells (MSCs) and their secretome-based therapeutic products. In the recent issue of World Journal of Stem Cells , Dam et al reinforce this paradigm by showing that MSCs derived from different adipose fractions share core phenotypic characteristics yet display source-dependent paracrine signatures - most notably in their differential growth factor profiles - that critically influence therapeutic behavior. From the perspective of oral and maxillofacial surgery, tissues routinely discarded during clinical procedures - including dental pulp, exfoliated deciduous teeth, periodontal ligament, and apical papilla - represent accessible and ethically favorable sources enriched with potent MSC populations. Owing to their neural crest origin, dental-derived MSCs exhibit unique proliferative dynamics and a distinct secretome composition, positioning them as strong candidates for next-generation cell-free regenerative strategies. Reframing these tissues as regenerative assets enables new opportunities for biobanking, mechanistic exploration, and precision engineering of MSC secretomes to improve therapeutic consistency. Progress in this direction will require harmonized isolation standards and systematic characterization of secretome heterogeneity to support the clinical translation of these unconventional yet highly valuable MSC reservoirs into deployable regenerative products.
BACKGROUND Gastroesophageal reflux disease (GERD) is associated with esophageal dysmotility, leading to impaired acid clearance and persistent symptoms. Mesenchymal stem cell (MSC) therapy holds promise for tissue regeneration and functional restoration. AIM To investigate the therapeutic efficacy and underlying molecular mechanisms of MSC treatment on esophageal dysmotility in a rat model of GERD and in human esophageal smooth muscle cells (HESMCs). METHODS A rat model of chronic GERD was established surgically. Rats were treated with human umbilical cord-derived MSCs via combined intravenous and local injection. Esophageal contractility was measured ex vivo . HESMCs were used for in vitro studies, including a senescence model induced by tumor necrosis factor (TNF)-α and MSC co-culture. Assessments included histology, senescence-associated β-galactosidase staining, immunohistochemistry, western blotting, intracellular Ca2+ imaging, small interfering RNA-mediated knockdown, and transcriptomic sequencing. RESULTS In vivo , GERD rats exhibited significantly reduced esophageal contractility, increased cellular senescence (β-galactosidase positivity), elevated TNF-α, decreased interleukin-10, and dysregulated expression of smooth muscle contraction-related proteins (decreased myosin light chain kinase, increased myosin phosphatase target subunit 1) and Ca2+ channels (decreased CACNA1C). MSC treatment restored esophageal contractility, mitigated senescence, normalized inflammatory markers, and reversed the protein dysregulation. In vitro , MSC co-culture effectively counteracted TNF-α-accelerated senescence in HESMCs, upregulated contractile proteins and ion channels (anoctamin 1, calcium voltage-gated channel subunit alpha1 C), and enhanced intracellular Ca2+ concentration. Mechanistically, MSCs modulated DNA methyltransferase 3a (DNMT3a) and hypoxia-inducible factor 1 alpha (HIF1α) pathways; inhibition of DNMT3a suppressed HIF1α, while HIF1α overexpression upregulated contractile proteins, establishing an MSC-DNMT3a-HIF1α axis. Transcriptomic analysis confirmed global gene expression changes in GERD and highlighted MSC-mediated modulation of inflammatory, signaling, and muscle-related pathways. CONCLUSION In conclusion, MSCs offer a potent therapeutic strategy for GERD-associated esophageal dysmotility by restoring smooth muscle function, alleviating senescence, and remodeling molecular pathways, primarily via a novel DNMT3a-HIF1α signaling cascade.
BACKGROUND Bone marrow-derived mesenchymal stem cells (BMSCs) are a promising therapy for ulcerative colitis (UC). However, their clinical benefit is limited by inefficient homing to the inflamed colonic mucosa. Improving the migration of BMSCs to sites of intestinal inflammation remains a key challenge in the development of cell-based treatments for UC. Tongxie Yaofang (TXYF), a traditional Chinese medicine formula, has been shown to relieve symptoms in UC patients. Our previous in vitro studies also showed that TXYF enhances the migratory capacity of BMSCs. However, whether TXYF enhances the therapeutic effect of BMSCs transplantation in UC, and the mechanisms involved, remain unclear. AIM To determine whether TXYF promotes the homing of BMSCs and improves experimental colitis, and to explore the underlying mechanisms. METHODS BMSCs from Sprague-Dawley rats were characterized via flow cytometry, and TXYF’s effects on migration were evaluated using scratch and Transwell assays. In a colitis model, the synergistic efficacy of TXYF and BMSCs was assessed through disease activity index, histology, immunohistochemistry, tracing, reverse transcription-quantitative polymerase chain reaction, and western blotting. Furthermore, the stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis was investigated using specific antagonists to elucidate the molecular mechanisms of this combinatorial therapy. RESULTS TXYF promoted the in vitro migration of BMSCs. In vivo , the combination of TXYF with BMSCs transplantation alleviated colitis symptoms in rats, improving inflammatory responses, colonic tissue damage, and mucosal barrier function. Our findings suggest that TXYF may enhance the migratory capacity of BMSCs by modulating the SDF-1/CXCR4 axis, thereby increasing their homing to the colonic mucosa. CONCLUSION This study demonstrates that TXYF can enhance the homing efficiency of exogenous BMSCs to the colonic mucosa, likely through the SDF-1/CXCR4 axis, which contributes to the mitigation of experimental colitis.
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.
Mesenchymal stem cells (MSCs) hold great promise for tissue repair and regeneration. The therapeutic efficacy of MSCs depends on the precise regulation of their proliferation and differentiation. In vivo , this process is synergistically modulated by extracellular matrix-derived biochemical cues and mechanical stress-dominated biophysical stimuli. However, traditional two-dimensional culture systems fail to replicate the complex three-dimensional microenvironment. In addition, population-averaged assays are often confounded by cellular heterogeneity and paracrine effects, which notably limits our mechanistic understanding of MSC fate determination. Microfluidic techniques, with high throughput, high accuracy and integration, provide powerful tools to overcome these limitations. In this review, we summarize recent research progress in the use of microfluidic techniques to investigate the mechanisms of MSC regulation. We outline the roles of biomaterials and mechanical stress in MSC-mediated repair processes, and highlight typical applications of microfluidic techniques in cell sorting and heterogeneity analysis, precise loading of biomaterials and mechanical stress, and dynamic phenotypic tracking of MSCs. We then discuss the current challenges and future directions in stem cell therapy, providing a methodological framework for MSC investigation and accelerating clinical translation.
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.
Periodontitis is a highly prevalent chronic inflammatory disease characterized by progressive destruction of periodontal supporting tissues and remains difficult to treat due to inflammation-induced impairment of regenerative responses. Persistent inflammatory niches suppress mesenchymal stem cell function, limiting the effectiveness of current regenerative therapies. Therefore, identifying factors that restore stem cell activity under inflammatory conditions is of significant clinical importance. We read with interest the study by Zhao et al entitled “Epiregulin enhances periodontal tissue regeneration by promoting bone marrow mesenchymal stem cell functions under inflammatory niches”. This article highlights the regenerative potential of epiregulin, which enhances bone marrow mesenchymal stem cell proliferation, migration, and osteogenic differentiation under inflammatory stress by activating the epidermal growth factor receptor-extracellular signal-regulated kinase signaling pathway, thereby promoting periodontal bone regeneration.
BACKGROUND Immunoglobulin A nephropathy (IgAN), a common primary glomerular disease, may progress to end-stage renal disease (ESRD). Stem cells regulate renal repair by countering mesangial injury, but the prognostic value very small embryonic-like stem cells (VSELs) and their synergy with complement/inflammatory biomarkers in IgAN remain unclear. Single-pathway biomarkers are inaccurate for ESRD prediction, and combined stem cell-complement/inflammatory risk stratification awaits validation. AIM To clarify the independent prognostic value of VSELs, complement factor I (CFI), C3a, and tumor necrosis factor-α (TNF-α) in IgAN patients and explore whether their combined detection can improve the accuracy of ESRD prediction. METHODS A retrospective analysis was conducted on 255 IgAN patients from our hospital, who were stratified into ESRD (31 cases) and non-ESRD (224 cases) groups based on follow-up outcomes. Complement alternative pathway indices included complement factor B, CFI, C3a, complement factor H, and sC5b-9; inflammatory biomarkers included monocyte chemoattractant protein-1, interleukin-6, TNF-α, B-cell activating factor, and C-X-C motif chemokine ligand 10; stem cell indicators included VSELs, hematopoietic stem cells, and endothelial progenitor cells. Statistical methods included t -tests, χ 2 tests, Spearman correlation, Logistic regression, receiver operating characteristic curves, and Kaplan-Meier survival analysis. RESULTS IgAN patients in ESRD had lower complement factor B, CFI, C3a, and higher monocyte chemoattractant protein-1, interleukin-6, TNF-α, and VSELs compared to non-ESRD (all P < 0.001), with CFI, C3a, TNF-α, and VSELs as independent ESRD predictors (all P < 0.05). The combined detection of CFI, TNF-α, and VSELs showed a higher predictive value for ESRD [area under the curve (AUC) = 0.916] than single indicators (CFI: AUC = 0.660; TNF-α: AUC = 0.818; VSELs: AUC = 0.749). Spearman correlation analysis revealed that VSELs were weakly positively correlated with CFI and TNF-α, while estimated glomerular filtration rate was positively correlated with CFI and negatively correlated with TNF-α (all P < 0.05). High VSELs indicated poorer renal prognosis (P < 0.001), with no significant differences in renal survival for CFI or TNF-α (all P > 0.05). CONCLUSION VSELs, along with CFI and TNF-α, are independent predictors of ESRD in IgAN patients, with VSELs providing a more reliable indicator of poor renal prognosis. Their combined detection achieves high predictive accuracy (AUC = 0.916), offering a non-invasive prognostic tool independent of Oxford classification features, thus enhancing risk stratification and individualized intervention strategies.
In this letter, we comment on the study by Jiang et al published in the recent issue of the World Journal of Stem Cells , which explores a combined therapeutic approach of exercise with induced pluripotent stem cells (iPSCs) for Parkinson’s disease (PD) using a mouse model. Currently, PD is primarily treated symptomatically as there are no treatment options available to prevent or cure it. While previous studies have examined exercise and iPSCs individually for PD, there is limited research on using them concurrently. Jiang et al aimed to evaluate this combined treatment method and investigate the underlying mechanisms. The results of this study indicate a synergistic relationship between exercise and iPSCs, demonstrating improved motor symptoms, and notably, elevated levels of proteins thought to be significant factors in the differentiation of dopaminergic neurons. This emphasizes that more research is needed to critically evaluate the underlying mechanisms of PD and neuronal differentiation in the hopes of developing effective and sustainable treatment options.
BACKGROUND Periodontitis is a prevalent chronic inflammatory disease whose progression can lead to the disrupted periodontal structures and subsequent tooth loss, severely impacting patients’ lives. Hence, exploring effective treatments for periodontitis is crucial. Periodontal ligament stem cells (PDLSCs) show promise for regenerating periodontal and alveolar bone tissues. Understanding the molecular mechanisms that control the osteogenic differentiation of PDLSCs is essential for developing regenerative therapies for periodontitis. Circular RNAs (circRNAs) are a novel type of noncoding RNA that form closed loops and are more stable than linear RNAs. Nevertheless, the relationship between circRNAs, periodontitis, and the osteogenic differentiation of PDLSCs has not been extensively studied. AIM To explore the roles of circRNA ADP-ribosylation factor 3 (circARF3) in the osteogenic differentiation of PDLSCs and periodontitis. METHODS Quantitative real-time polymerase chain reaction was utilized to compare RNA expression in periodontal ligament tissues from periodontitis patients and healthy individuals. PDLSCs were isolated, and flow cytometry was used to identify their surface markers. Alizarin red staining and alkaline phosphatase staining were performed to assess PDLSC osteogenic differentiation. Western blotting was employed to measure the expression of proteins related to osteogenic differentiation, including Runx2, Osterix, Osteocalcin, and Col1a1. The ENCORI website was applied to predict the interaction between miR-27b-3p and circARF3 and the 3’ untranslated region of Yes associated protein 1 (YAP1), and this interaction was validated using luciferase reporter gene assays, RNA immunoprecipitation, and RNA pulldown. RESULTS circARF3 expression was decreased in periodontal ligament tissues of patients with periodontitis compared with healthy individuals (P < 0.01). circARF3 knockdown resulted in decreased alkaline phosphatase activity, alizarin red staining, and osteogenic gene expression (P < 0.01). miR-27b-3p directly binds to circARF3 and the 3’ untranslated region of YAP1. Overexpression of miR-27b-3p mimicked, and depletion of YAP1 reversed, the effect of circARF3 on PDLSC osteogenic differentiation (P < 0.01). CONCLUSION Depletion of circARF3 suppresses PDLSC osteogenic differentiation in periodontitis via the miR-27b-3p/YAP1 axis.
Knee osteoarthritis (OA) represents a progressive degenerative joint disorder characterized by articular cartilage degradation, chronic synovial inflammation, and pathological subchondral bone remodeling. Despite its prevalence and substantial socioeconomic impact, current therapeutic strategies remain predominantly symptomatic, failing to address the underlying disease mechanisms. Mesenchymal stromal cells (MSCs) have emerged as promising therapeutic agents, with accumulating evidence suggesting their efficacy stems primarily from paracrine signaling rather than direct cellular differentiation. The MSC-derived secretome, comprising extracellular vesicles (particularly exosomes), growth factors, cytokines, and immunomodulatory proteins, represents a sophisticated cell-free therapeutic platform capable of simultaneously targeting multiple pathological pathways in OA. This narrative review synthesizes current knowledge regarding the molecular mechanisms through which MSC-derived secretomes modulate the OA microenvironment, critically analyzes preclinical and emerging clinical evidence, and addresses the formidable challenges confronting clinical translation. We examine the secretome’s role in chondroprotection, immunomodulation, and subchondral bone homeostasis, while identifying critical gaps in standardization, delivery optimization, and regulatory frameworks that must be addressed to realize the full therapeutic potential of this promising regenerative strategy.
