Bone marrow-derived leptin receptor-expressing (LepR[+]) stromal cells (LepR[+] BMSCs) have been identified as the primary source of osteoblasts, adipocytes, and fibroblasts in the bone marrow, and they play key roles in the maintenance of the bone marrow microenvironment; however, research on the fate and immunomodulatory changes of human LepR[+] BMSCs is limited. Here, we isolated LepR[+] BMSCs from a young donor and studied their fate changes of osteogenic, adipogenic, myogenic differentiation, and immunomodulation with or without CXM102, a novel compound that we have previously demonstrated its anti-osteoporotic effects in mice. Our results showed that CXM102 facilitated a preferential lineage shift toward osteogenesis from adipogenesis of LepR[+] BMSCs in vitro, as evidenced by increased RUNX 2 expression and decreased PPARγ in a bivalent differentiation system. Moreover, interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were markedly downregulated in HS-5 stromal cells cocultured with conditioned medium from CXM102-treated LepR[+] BMSCs. Furthermore, CXM102 also inhibited collagen I deposition in LepR[+] BMSCs when induced into myogenesis. These results demonstrated that CXM102 could promote osteogenesis, but inhibit adipogenesis and myogenesis of LepR[+] BMSCs, while also showing benign immunomodulation in vitro.

Stem cell-associated microRNAs (miRNAs) have emerged as pivotal regulators of osteogenesis, influencing lineage commitment, differentiation, and skeletal tissue homeostasis. Their dysregulation has been increasingly linked to a spectrum of osteogenic disorders, including osteoporosis, osteoarthritis, and impaired fracture healing. This narrative review synthesizes current evidence on the diagnostic potential of stem cell-associated miRNAs in bone-related pathologies. We highlight their roles in modulating osteoblast and osteoclast activity, maintaining mesenchymal stem cell fate, and orchestrating signaling pathways such as Wnt/β-catenin, bone morphogenetic protein, and Notch. Particular emphasis is placed on circulating miRNAs as minimally invasive biomarkers, offering prospects for early detection, disease stratification, and monitoring therapeutic response. Furthermore, we discuss methodological advances in miRNA profiling, challenges in clinical translation, and the need for standardized validation frameworks. By integrating molecular insights with translational perspectives, this review underscores the promise of stem cell-associated miRNAs as diagnostic tools in osteogenic disorders, while identifying critical gaps that must be addressed to enable their incorporation into precision medicine strategies.

Hematopoietic stem cell (HSC) has self-renewal and multilineage differentiation capacities. They sustain lifelong homeostasis and repair of damaged tissues, serving as the core cellular foundation for long-term homeostasis and regenerative repair. Maintaining HSC stemness is essential for normal hematopoiesis; this is not a static property but a dynamically regulated process that directly governs the stable operation of regular hematopoiesis. Recent studies show that HSC quiescence, self-renewal, and lineage differentiation are coordinately controlled by multiple signaling cues. Transcription factor networks, the extracellular matrix, metabolic reprogramming, and epigenetic modifications interact to form a regulatory network that governs stemness maintenance. Under physiological conditions, these factors establish stemness homeostasis; when aberrantly remodeled, they drive diseases such as leukemia and bone marrow failure. This review summarizes the factors that modulate HSC function and stemness during genetic information transmission, and discusses their biological significance. It further elaborates on the regulatory network, compares its distinct patterns in physiological versus pathological states, and explores its translational clinical value. Ultimately, this work aims to provide basic researchers with an integrated conceptual framework and to offer feasible forward-looking strategies for clinical translation.

Dental pulp stem cells (DPSCs), stem cells from human exfoliated deciduous teeth (SHED), and extracellular vesicles (EVs) show regenerative potential, but clinical translation depends on a reproducible product-process-procedure system. This systematic scoping review mapped how DPSC- and EV-containing dental products are defined, manufactured, formulated, dosed, delivered, monitored, and regulated. Following Joanna Briggs Institute guidance (JBI) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR), an umbrella-assisted strategy combined two recent high-coverage reviews with a targeted update through July 15, 2026. Data were charted for source, characterization, carrier, dose, delivery, visualization, safety, outcomes, and manufacturing readiness; a nine-domain review-level framework (Translational Readiness Appraisal for Dental cell and EV products) summarized relative maturity without serving as a validated clinical score. The map comprised 52 unique primary reports and nine methodological or secondary sources. Scaffold-based DPSC/SHED studies generally favored cell-containing constructs, but most were heterogeneous short-term animal experiments. Small human studies of autologous DPSC or SHED products reported encouraging feasibility and few serious safety signals, yet were underpowered for effectiveness or uncommon harms. Dental EV evidence remained predominantly preclinical; isolation, particle-normalized dosing, potency, storage, biodistribution, and batch comparability were frequently incomplete. Magnification was not consistently standardized as a delivery variable. Relative readiness was highest for autologous DPSC pulp products, intermediate for DPSC-scaffold bone or periodontal products, and low for dental EV products. Translation now requires indication-specific potency assays, carrier-product codevelopment, dose-response and biodistribution studies, documented delivery fidelity, standardized outcomes, long-term safety follow-up, and explicit good manufacturing practice (GMP) and regulatory strategies before confirmatory trials.

The modulation of Notch and Wnt signaling was evaluated for its ability to promote the differentiation and maturation of hair cell (HC)-like cells in otic organoids derived from mouse embryonic stem cells (mESCs). Using R1/E mESCs, we generated otic organoids and treated them with the Notch pathway inhibitor (γ-secretase inhibitor, DAPT) and the Wnt signaling agonist (CHIR99021) during two-time windows: days (D) D12-D18 (early treatment) or D28-D34 (late treatment). Among the late treatment conditions, lower concentration (5 μM DAPT and 2.5 μM CHIR99021) yielded greater expression of MyoVIIa and Atoh1 compared with higher doses (10 and 5 μM, respectively). Ultrastructural analysis by transmission electron microscopy further demonstrated that late treatment with lower-dose DAPT and CHIR99021 generated HC-like cells harboring longer and more prominent stereocilia-like bundles than those observed in other conditions. In contrast, early treatment produced HCs arranged in a typical otic organoid pattern, resulting in a more morphologically stable but less robustly induced HC-like population. These findings indicate that temporally and dose-controlled modulation of Notch and Wnt signaling efficiently enhances HC-like cell differentiation and stereocilia maturation in mESC-derived otic organoids, providing a useful platform for future studies in inner ear regeneration and cell-based therapies.

Human brain organoids have evolved from early neurodevelopmental models into platforms for therapeutic discovery. Here, we highlight two cases in which organoid-derived findings enabled FDA-approved clinical trials. Patient-derived organoids modeling Pitt-Hopkins syndrome revealed human-specific, TCF4-dependent abnormalities and supported the development of a regulated AAV gene therapy. In parallel, Rett syndrome organoids cultured aboard the International Space Station uncovered space-induced neural senescence, characterized by retroelement-associated neuroinflammation, prompting evaluation of antiretroviral therapy. These examples illustrate how organoids can reveal disease mechanisms that are inaccessible or incompletely reproduced in animal models, while animal studies remain essential for validation and safety assessment. As the field advances, matching model complexity to experimental purpose-and ensuring reproducibility, scalability, and accessibility-will be critical. Human brain organoids are crossing a translational threshold, emerging as engines of therapeutic discovery and gateways to clinical intervention.

Bronchopulmonary dysplasia (BPD) is a major complication of prematurity with limited disease-modifying therapies. We evaluated umbilical cord-derived cell-based interventions for BPD and related complications in preterm infants. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020-based systematic review and meta-analysis were registered in PROSPERO. PubMed, Cochrane Library, Web of Science, CNKI, and Wanfang were searched from inception to June 14, 2026. Comparative clinical studies of umbilical cord-derived cell-based interventions in preterm infants at risk of or diagnosed with BPD were included. Outcomes included BPD, BPD severity, death, persistent pulmonary hypertension of the newborn (PPHN), patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), late-onset sepsis (LOS), and adverse events (AEs). Bayesian random-effects meta-analysis used a binomial-normal hierarchical model to estimate pooled odds ratios (ORs), 95% credible intervals (CrIs), prediction intervals, and heterogeneity. Twelve studies were included. Umbilical cord-derived cell-based interventions showed a possible protective effect on overall BPD (OR, 0.48; 95% CrI, 0.14-1.20). Stronger associations were observed for severe BPD (OR, 0.17; 95% CrI, 0.01-0.85), moderate or severe BPD (OR, 0.28; 95% CrI, 0.09-0.70), and ROP stage ≥3 (OR, 0.17; 95% CrI, 0.02-0.65). No conclusive benefit or harm was observed for death, PPHN, PDA, IVH, NEC, or LOS. No treatment-related serious AEs were identified. However, prediction intervals were generally wide, and the certainty of evidence was low to very low for most outcomes. Umbilical cord-derived cell-based interventions may reduce the risk of moderate or severe BPD in preterm infants, with an additional potential benefit for ROP stage ≥3. Current evidence remains limited, and larger randomized trials with standardized outcomes and long-term follow-up are needed.

Stroke is a major cerebrovascular event leading to high rates of disability and mortality around the world. Fundamental research has elucidated the pathological processes of stroke to inform effective therapeutic strategies. Mitochondria, as the primary energy source for neurons, play a pivotal role in maintaining nervous tissue homeostasis, and disruptions in their function contribute to mitochondrial dysfunction, neuronal injury, and apoptosis. Exosomes, particularly those derived from mesenchymal stem cells (MSCs), exhibit remarkable potential as an ideal therapeutic modality. Owing to their nanoscale dimensions and bioactive cargo, exosomes can traverse the blood-brain barrier and modulate injury outcomes in the central nervous system (CNS). This review synthesizes prior studies to delineate the current status and therapeutic promise of MSC-derived exosomes as a cell-free approach for stroke management.

Aging causes a decrease in cardiac function in living organisms. Although stem cell transplantation shows therapeutic potential for aging hearts, distinct types of evidence have indicated that preconditioning is an effective therapeutic strategy for stem cells to improve tissue regenerative function. This study investigates the therapeutic effect of mesenchymal stem cell preconditioning with curcumin and miR-3575 in the treatment of an aging heart. Cell models have confirmed that preconditioning with curcumin enables stem cells to increase cell viability and CXCR4/p-Akt signal activation. Intervention of miR-3575 mimic significantly enhances viability and CXCR4/p-Akt signal in curcumin preconditioned stem cells. The beneficial effects are suppressed in curcumin preconditioned stem cells receiving miR-3575 inhibitor. The aging animal groups were designed to test the above hypothesis including Aging (rats with 20 months), Aging + ADSC (aging rats receiving adipose-derived stem cells), Aging + Cur-ADSC (aging rats receiving curcumin preconditioned ADSC), Aging + miR mic-ADSC (aging rats receiving miR-3575 mimic preconditioned ADSC), and Aging + miR inh-ADSC (aging rats receiving miR-3575 inhibitor preconditioned ADSC). Compared to Aging, Aging + ADSC slightly improves cardiac function, structure, and pathological protein markers, whereas Aging + Cur-ADSC and Aging + miR mic-ADSC significantly improve the above pathological status. On the other hand, the improvement is suppressed in the ADSC group preconditioned with a miR-3575 inhibitor (Aging + miR inh-ADSC). These findings suggest that ADSC preconditioning with curcumin and miR-3575 shows clinical potential in the treatment of heart failure induced by aging.

Recent whole-genome, lineage-tracing, single-cell, and spatial studies have reshaped our understanding of tumor evolution, revealing that cancers can arise from polyclonal populations, undergo decades-long genomic instability before clinical detection, and progress through dynamic changes in subclonal composition, cellular state, and ecological organization. These findings challenge the assumption underlying morphology-based prediction models that metastatic risk can be inferred from static histological features alone. Here, we revisit lymph-node metastasis prediction in colorectal cancer through clonal ecology, integrating computational pathology with evolutionary oncology. Drawing on the subclonal switchboard model proposed in 2012 and subsequent artificial intelligence (AI)-enabled approaches for tracking dominant and dormant subclones, we synthesize evidence that metastatic potential reflects clonal ancestry, evolutionary timing, spatial niche architecture, cellular plasticity, intercellular interactions, dormancy, and treatment-driven shifts in subclonal fitness. We define five complementary methodological pillars for operationalizing clonal ecology: single-cell transcriptomics for resolving rare subclones, evolutionary trajectories, and adaptive cell states; lineage tracing and phylogenetics for reconstructing clonal ancestry and divergence; spatial transcriptomics and genomics for mapping subclonal geography and tumor-stromal-immune interactions; longitudinal liquid biopsy surveillance for monitoring residual disease, clonal turnover, and emerging resistance; and AI-enabled multimodal integration for connecting histopathology, genomics, spatial biology, and longitudinal data into predictive ecological-state models. Multiple-instance learning and pathology foundation models provide scalable computational foundations for evolution-aware prediction. Translationally, dormant subclones represent actionable reservoirs of recurrence. A longitudinal clinical and experimental study of KMT2A-rearranged acute myeloid leukemia further supports central predictions of the subclonal switchboard framework by demonstrating treatment-associated shifts in subclonal dominance, persistence of cryptic adaptive programs, and ecological rewiring during resistance and relapse. We propose clonal ecology as a measurable dimension for extending morphology-driven prediction toward integrative models that anticipate evolutionary transitions, identify therapeutic windows, and proactively constrain adaptive tumor ecosystems before resistant or metastatic subclones achieve clinical dominance.

Despite currently available treatment options for moderate-to-severe atopic dermatitis (AD), some patients fail to achieve adequate disease control. Emerging evidence suggests that mesenchymal stem cells (MSCs) may represent a promising therapeutic option. This systematic review and meta-analysis included four randomized controlled trials (RCTs) and one non-randomized clinical trial. Eligible studies evaluated patients with moderate-to-severe AD treated with MSCs derived from human umbilical cord blood, autologous adipose tissue, and allogeneic bone marrow. PubMed, Embase, and Cochrane were searched from inception to December 2025. Primary outcomes included the proportion of patients achieving ≥50% and ≥75% improvement from baseline in the Eczema Area and Severity Index (EASI) and safety outcomes. The meta-analysis included 236 participants. The pooled EASI-50 response rate at week 12 was 46.76% (95% confidence interval [CI]: 32.36% to 61.72%). EASI-75 response rates were 17.41% (95% CI: 5.56% to 43.03%) at week 12 and 23.97% (95% CI: 16.48% to 33.50%) at week 16. The pooled incidence of treatment-emergent adverse events was 26.86% (95% CI: 19.56% to 35.68%), with infections and infestations 7.97% (95% CI: 4.11% to 14.88%) and gastrointestinal disorders 3.52% (95% CI: 1.33% to 9.01%) being the most frequently reported. MSC-based therapy shows early promise as a potential treatment for moderate-to-severe AD, offering a possible alternative to traditional therapies. However, the current evidence is largely based on small clinical trials, underscoring the necessity for large-scale RCTs to establish the efficacy and safety of MSC-based therapy in broader patient populations.

The cochlear nucleus (CN) is the first central relay of auditory information, receiving input from spiral ganglion neurons (SGNs) through specialized synapses whose molecular regulation remains incompletely defined. Here, we examined the role of Progranulin (Grn) in a stem cell-based CN synaptogenesis using an in vitro coculture model. DsRed-expressing mouse embryonic stem cells were differentiated into SGN-like neurons (deSGNs) and cocultured for 4 days with primary CN neurons isolated from postnatal days 3-6 wild-type (Grn[+/+]) or Grn-deficient (Grn[-/-]) mice. Cocultures containing Grn[+/+] mouse CN neurons exhibited abundant neurite interactions and synaptic puncta between deSGNs and CN neurons. In contrast, neural connectivity and synaptic puncta were markedly reduced in cocultures with Grn[-/-] mouse CN neurons. Supplementation with recombinant Progranulin protein significantly restored neurite connectivity and synaptic puncta formation in Grn[-/-] mouse CN neuron cocultures. Dose-response analysis further demonstrated that Progranulin concentrations of 0.1-1 µM effectively rescued neurite connection and synaptic features to levels comparable to those observed in Grn[+/+] mouse CN neuron cocultures. These findings identify Grn as a critical regulator of CN synapse formation in vitro and provide mechanistic insight relevant to stem cell-based strategies aimed at reconstructing SGN-CN synapses for future auditory repair.

Prevascularized cell sheets are widely used in tissue engineering; however, enhancing their angiogenic potential within hypoxic microenvironments remains a significant challenge. In this study, we employed genetic manipulation to upregulate Sestrin2 (SESN2) expression in human umbilical vein endothelial cells (HUVECs) and investigated its effect on their angiogenic potential under hypoxic conditions. Transwell migration and Matrigel tube formation assays confirmed that SESN2 significantly promoted proliferation, migration, and tube formation of HUVECs under hypoxia, thereby enhancing angiogenesis. Furthermore, HUVECs overexpressing SESN2 were seeded onto cell sheets, and immunofluorescence staining for CD31 revealed increased lumen formation compared with the control group. SESN2 was also found to promote the secretion of vascular endothelial growth factor A and platelet-derived growth factor BB in vitro. Subsequent subcutaneous implantation studies demonstrated that prevascularized cell sheets with SESN2 overexpression enhanced angiogenesis and promoted the formation of functional blood vessels. In conclusion, SESN2 improves the vascularization capacity of tissue-engineered grafts in hypoxic environments, thereby facilitating successful transplantation of engineered tissues.

Alzheimer's disease (AD) is the leading cause of dementia, and effective disease-modifying therapies remain limited. Mesenchymal stem cells (MSCs) have shown therapeutic potential because of their neuroprotective and immunomodulatory properties, but clinical evidence remains inconclusive. We systematically evaluated the efficacy and safety of MSC therapy in AD. Following the PRISMA 2020 guidelines and a PROSPERO-registered protocol (CRD420261329891), we searched PubMed, the Cochrane Library, Embase, Web of Science, CNKI, and Wanfang from inception to March 1, 2026. Clinical studies of patients with primary AD treated with MSCs were included. Outcomes covered cognition, daily function, neuropsychiatric symptoms, biomarkers, imaging findings, and adverse events. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using R. Risk of bias was assessed with the RoB 2 tool, and evidence certainty was assessed with GRADE. Six studies involving 196 patients were included. Overall analyses showed no significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) or Mini-Mental State Examination (MMSE) at 12-16 weeks or 24-26 weeks after MSC treatment versus placebo, with substantial heterogeneity. Dose-stratified analyses suggested significant benefits of low-dose MSCs on ADAS-Cog (SMD = -1.33, 95% CI: -2.35 to -0.31) and MMSE (SMD = 2.59, 95% CI: 0.52-4.66). MSC therapy significantly improved Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; SMD = 3.27, 95% CI: 1.79-4.75), but not Neuropsychiatric Inventory (NPI) or Quality of Life in Alzheimer's Disease (QOL-AD) scale. Biomarker analyses showed no significant overall effects on Aβ42 or total tau, although subgroup analyses suggested possible increases in Aβ42 and reductions in total tau at certain doses. Imaging data from two studies indicated potential protective effects on hippocampal atrophy. MSC therapy was generally well-tolerated, although intracerebroventricular administration was associated with more transient adverse events. Evidence certainty was low to very low for most outcomes. MSC therapy for AD appears feasible and relatively safe, with potential cognitive and disease-modifying effects. However, current clinical evidence remains insufficient to confirm its efficacy.