Stem Cell Res Ther [JOURNAL]
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200 papers
Spatiotemporal single-cell atlas of suture stem cell dynamics in craniosynostosis.
Chen X, Lai C, He T … +2 more , Chen Z, Jin X
Stem Cell Res Ther · 2026 May · PMID 42071254 · Full text
BACKGROUND: Craniosynostosis is a congenital disorder characterized by premature suture fusion and aberrant skull morphogenesis. The cellular dynamics and regulatory mechanisms of suture mesenchymal stem cells (SuSCs) in...
BACKGROUND: Craniosynostosis is a congenital disorder characterized by premature suture fusion and aberrant skull morphogenesis. The cellular dynamics and regulatory mechanisms of suture mesenchymal stem cells (SuSCs) in this disease remain poorly defined. METHODS: We integrated single-cell RNA sequencing and 2-μm-resolution Visium HD spatial transcriptomics to build a spatiotemporal atlas of coronal suture cells in Fgfr2 mice, a murine model recapitulating human Crouzon syndrome, alongside wild-type controls across three key developmental stages (E14.5, E18.5, and P3). To obtain near single-cell spatial resolution, we created SpatialCell, which combines morphology-based segmentation and machine-learning classification using a reference trained on our single-cell datasets. RESULTS: The atlas reveals stage-specific remodeling of SuSC niches and a shift of SuSC spatial associations toward osteogenic mesenchyme in craniosynostosis. Along the SuSC-to-osteoblast trajectory, pre-osteoblasts were depleted earlier than upstream SuSCs, and SuSCs displayed premature acquisition of osteogenic programs near the suture midline. Temporal Gene Ontology patterns indicated early extracellular-matrix disruption, mid-gestation chondrogenic activation, and postnatal mineralization. Network analysis nominated Foxa3 as a candidate regulator in SuSC subsets; siRNA knockdown of Foxa3 reduced ex vivo mineralization in the craniosynostosis background. Spatial communication analyses implicated signals from suture meningeal fibroblasts and immune cells that converge on SuSC fate. CONCLUSIONS: Our results support a model where craniosynostosis may involve disrupted temporal coordination of developmental programs, not merely accelerated bone formation. The atlas and analytic framework pinpoint when and where SuSC fate diverges, propose Foxa3 as an intervention target, and provide a high-resolution resource for mechanistic and therapeutic exploration.
Engineered cardiac patches from hiPSC-derived cardiomyocytes.
Jawad J, Khan MZ, Jabsheh T … +1 more , Javidi D
Stem Cell Res Ther · 2026 May · PMID 42069703 · Full text
BACKGROUND: Heart failure remains a leading global cause of morbidity and mortality, with limited capacity for myocardial regeneration following infarction. Human induced pluripotent stem cell-derived cardiomyocytes (hiP...
BACKGROUND: Heart failure remains a leading global cause of morbidity and mortality, with limited capacity for myocardial regeneration following infarction. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have become a promising therapeutic resource due to their scalability, differentiation potential, and immunologic adaptability. Engineered cardiac patches, three-dimensional constructs of hiPSC-CMs combined with supporting cells and scaffolds, offer a strategy to deliver organized myocardium directly to injured hearts, overcoming the limitations of cell injection therapies. SCOPE OF REVIEW: This review synthesizes evidence from 2010 to early 2025, spanning rodent, porcine, and non-human primate models, as well as the first clinical trials of hiPSC-CM patches. We highlight recent advances in maturation protocols, vascularization strategies, and scaffold engineering, while discussing two distinct translational paradigms: short-term paracrine support versus long-term remuscularization under sustained immunosuppression. RESULTS: Preclinical studies show that engineered patches improve graft survival, with engraftment rates ranging from 5 to 15%, alongside enhanced vascularization, electrical coupling, and left ventricular function. In large animal models, patches scaled to clinically relevant sizes achieved durable integration and improved hemodynamics. Of note, arrhythmogenic risk was lower than in intramyocardial injection models. Early human trials in Japan and Germany confirm feasibility and safety, with preliminary evidence of efficacy, including preliminary evidence of improved left ventricular ejection fraction and upgrades in NYHA functional class. Immunogenicity, graft maturation, and manufacturing scalability remain key hurdles, though innovations such as gene-edited hypoimmunogenic lines, multipronged maturation strategies, and bioreactor-based production offer potential solutions. CONCLUSIONS: Engineered hiPSC-CM cardiac patches represent a rapidly advancing frontier in regenerative cardiology. While early data indicate technical feasibility and measurable functional benefits, broader adoption will depend on resolving challenges of immune compatibility, arrhythmia prevention, and large-scale manufacturing. With coordinated progress in science, engineering, and regulation, cardiac patches may evolve into a transformative therapy for heart failure.
Refined detection of CD34⁺CD38⁻CD45RA⁺ leukemic stem cells using a single-tube flow cytometry assay and its strong association with measurable residual disease in acute myeloid leukemia: a retrospective cohort study.
Navidinia AA, Rostami S, Karami N … +9 more , Shemshadinia M, Patekhor HS, Hajaliaskari A, Mohammadi S, Rostami T, Barkhordar M, Vaezi M, Janbabaei G, Chahardouli B
Stem Cell Res Ther · 2026 May · PMID 42069652 · Full text
BACKGROUND: Leukemic stem cells (LSCs) are the cellular reservoir most strongly implicated in relapse of acute myeloid leukemia, yet their operational detection by multiparameter flow cytometry remains challenging becaus...
BACKGROUND: Leukemic stem cells (LSCs) are the cellular reservoir most strongly implicated in relapse of acute myeloid leukemia, yet their operational detection by multiparameter flow cytometry remains challenging because of immunophenotypic overlap with normal progenitors and variability across assays. Including CD45RA in the CD34⁺CD38⁻ gating strategy substantially improves discrimination between malignant and normal stem/progenitor populations and thus enables more precise LSC enumeration in a single-tube format. Given the clinical importance of accurately quantifying the LSC compartment, we evaluated a refined single-tube flow cytometry assay that incorporates CD45RA within the CD34 + CD38- gate to increase specificity for the leukemic stem compartment. METHODS: In a retrospective cohort of 109 AML bone marrow samples, measurable residual disease (MRD) was assessed with a conventional three-tube, 8-color panel and LSCs were enumerated using an adapted single-tube, 8-color panel defining LSCs as CD34 + CD38-CD45RA + . To ensure analytical reliability we applied a formal lower limit of quantification (LLOQ), defined empirically as a cluster of 50 CD45 + events; samples below the sample-specific LLOQ were not called positive. Positivity thresholds were set at ≥ 0.1% for MRD and ≥ 0.004% for LSCs. Group comparisons used the Mann-Whitney U test and associations were quantified by Pearson correlation. RESULTS: LSCs were detectable in 28/109 (25.7%) patients, while MRD positivity was observed in 37/109 (33.9%) patients. A robust association was demonstrated between LSC presence and MRD positivity (p = 0.00035). The LSC burden was significantly elevated in MRD-positive patients, and concomitantly, MRD levels were profoundly higher in patients harboring detectable LSCs (p = 2.01 × 10⁻⁹). A strong positive correlation was observed between LSC and MRD levels across the entire cohort (R = 0.66, p = 3.2 × 10⁻). LSC and MRD status were independent of sex, FLT3, or NPM1 mutation status. Immunophenotypic profiling of the LSC compartment revealed predominant aberrant co-expression of CD33 (89.3%) and a multi-marker cocktail (89.3%), with CD44 (67.9%) and CD123 (53.6%) also frequently observed. CONCLUSIONS: The implementation of a refined LSC detection assay, leveraging CD45RA gating and a stringent LLOQ, yields a specific and clinically actionable quantification of the LSC reservoir in AML. The strong correlation between the CD34 + CD38-CD45RA + LSC subset and MRD status suggests its potential as a complementary biomarker for residual disease monitoring; however, prospective validation in outcome-annotated cohorts is required to establish its prognostic utility and clinical applicability.
3D spheroids of umbilical cord-derived MSCs protect retinal pigment epithelium against oxidative and inflammatory injury by activating autophagy.
Xu Q, Li M, Li D … +3 more , Dai X, Zhang Y, Qu Y
Stem Cell Res Ther · 2026 May · PMID 42069635 · Full text
BACKGROUND: Age-related macular degeneration (AMD) is characterized by progressive retinal pigment epithelium (RPE) dysfunction driven by oxidative stress and chronic inflammation, in which NLRP3 inflammasome activation...
BACKGROUND: Age-related macular degeneration (AMD) is characterized by progressive retinal pigment epithelium (RPE) dysfunction driven by oxidative stress and chronic inflammation, in which NLRP3 inflammasome activation plays a critical role. Mesenchymal stem cells (MSCs) exhibit therapeutic potential, but their efficacy is limited by poor survival and reduced paracrine activity in hostile microenvironments. Here, we investigated whether three-dimensional (3D) spheroid culture enhances the protective effects of umbilical cord-derived MSCs (UC-MSCs) on RPE cells by promoting autophagy and suppressing inflammasome activation. METHODS: Human UC-MSCs were cultured as 3D spheroids or conventional 2D monolayers and applied in sodium iodate (NaIO)-induced oxidative injury models both in vitro and in vivo. Retinal morphology and function were assessed via histology and electroretinography, while NLRP3/caspase-1 activation, LC3-II/I ratios, and autophagy flux were quantified using immunofluorescence and Western blot. GO/KEGG enrichment was performed to identify pathways associated with 3D MSCs efficacy. Mechanistic involvement of autophagy was validated using 3-methyladenine (3-MA) and rapamycin. RESULTS: 3D MSCs formed compact spheroids exhibiting enhanced paracrine potential and significantly outperformed 2D MSCs in protecting RPE cells against NaIO-induced injury. In vivo, 3D MSC treatment preserved retinal structure, reduced RPE cell loss, and improved retinal function. In vitro, co-culture with 3D MSCs markedly improved ARPE-19 viability, reduced apoptosis, and modulated autophagy-related marker expression, as evidenced by increased LC3-II/I ratios. 3D MSCs significantly inhibited NLRP3 inflammasome activation and pro-inflammatory cytokine release, effects reversed by 3-MA and further enhanced by rapamycin. CONCLUSIONS: 3D spheroid culture substantially augments the therapeutic efficacy of UC-MSCs by boosting autophagy and suppressing NLRP3 inflammasome signaling, resulting in enhanced protection of RPE cells from oxidative and inflammatory injury. These findings provide preclinical evidence supporting 3D MSCs as a promising therapeutic strategy for AMD.
Generation and single-cell characterization of functional megakaryocytes derived from umbilical cord blood.
He Y, Liang Y, He J … +4 more , Shen Y, Wu Z, Pei S, Zhu F
Stem Cell Res Ther · 2026 May · PMID 42069610 · Full text
BACKGROUND: Generation of megakaryocytes (MKs) from stem cells in vitro to produce platelets (PLTs) is an appealing approach for providing an alternative source of PLTs. Understanding the transcriptomic characteristics o...
BACKGROUND: Generation of megakaryocytes (MKs) from stem cells in vitro to produce platelets (PLTs) is an appealing approach for providing an alternative source of PLTs. Understanding the transcriptomic characteristics of MKs in vitro is crucial for providing a theoretical foundation for producing functional MKs more efficiently in the future. METHODS: CD34 hematopoietic stem and progenitor cells (HSPCs) were separated from umbilical cord blood (UCB) and were induced to differentiate into MKs in vitro through a culture system. The phenotypes of these cells cultured for different durations were analyzed through flow cytometry. The mRNA expression levels of GATA1, GATA2, FOG1, NF-E2, FLI1, CD41, and CD61 at different time points were analyzed through quantitative PCR. The activation levels of PLTs in vitro and the PLTs produced in vivo were determined. The MK subpopulations were further analyzed through single-cell RNA sequencing (scRNA-seq). RESULTS: UCB-derived MKs exhibited typical characteristics of MKs in vivo, including morphology, polyploidy, and subcellular structure. The mRNA expression levels of GATA1, FOG1, NF-E2, FLI1, CD41, and CD61 on Days 10 and 14 were significantly greater than those on Day 4. CD62P expression on the surface of UCB-PLTs increased markedly in response to thrombin or TRAP6 stimulation. Humanized PLTs were also detected in the peripheral blood of NCG mice following the infusion of UCB-MKs. According to the results of the sc-RNAseq analysis, nine transcriptionally distinct clusters of UCB-MKs, labeled MK1-MK9, were identified, with only the MK9 population being related to immunity. The MK1-MK8 populations displayed typical MK characteristics and were the most prevalent subtypes. In addition, compared with hESCs, UCB-derived MKs exhibited a greater proportion of active-cycling MKs with strong differentiation potential. CONCLUSIONS: In conclusion, this study describes the biological functions and transcriptomic profile of MKs derived from UCB, which will aid in the further development of more efficient systems for generating MKs in vitro and promote their application in cellular therapy.
Efficacy and safety of stem cell therapy for dry eye disease: a systematic review and meta-analysis.
Chen KY, Chan HC, Chan CM
Stem Cell Res Ther · 2026 May · PMID 42067941 · Full text
INTRODUCTION: Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by loss of tear film homeostasis, inflammation, neurosensory abnormalities, and epithelial damage. Despite the availability of...
INTRODUCTION: Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by loss of tear film homeostasis, inflammation, neurosensory abnormalities, and epithelial damage. Despite the availability of topical immunomodulators and procedural interventions, a substantial proportion of patients with moderate-to-severe or refractory DED experience persistent symptoms and inadequate ocular surface recovery. Stem cell-based therapies, particularly mesenchymal stem cells (MSCs) and MSC-derived exosomes, have emerged as regenerative and immunomodulatory strategies aimed at restoring epithelial integrity and tear film stability rather than providing solely symptomatic relief. We conducted a systematic review and meta-analysis to evaluate the clinical efficacy and safety of stem cell and stem cell-derived therapies in human DED. METHODS: This study followed PRISMA 2020 guidelines and was prospectively registered in PROSPERO (CRD420251057372). Six databases were searched from inception to May 14, 2025. Eligible studies were peer-reviewed human clinical investigations evaluating stem cell-based interventions for DED and reporting objective efficacy outcomes such as Schirmer test, tear break-up time (TBUT), corneal fluorescein staining (CFS), or patient-reported outcomes including the Ocular Surface Disease Index (OSDI). Pooled mean differences (MDs) or standardized mean differences (SMDs) with 95% confidence intervals (CIs) were calculated. Statistical heterogeneity was assessed using the I² statistic. Risk of bias was evaluated using RoB 2 for randomized controlled trials and ROBINS-I for non-randomized studies. RESULTS: Six studies comprising 131 patients were included. Stem cell-based therapies demonstrated significant improvements in tear production, tear film stability, epithelial integrity, and symptom burden. Schirmer test improved by MD = 4.70 mm (95% CI, 4.18-5.22; p < 0.001; I² = 12.59%), indicating a consistent enhancement of aqueous tear secretion. TBUT showed a large standardized improvement with pooled SMD = 1.125 (95% CI, 0.821-1.428; p < 0.001), although randomized trials demonstrated smaller effect sizes than non-randomized studies. OSDI scores decreased by MD = -11.44 points (95% CI, -22.71 to -0.17; p = 0.047), reflecting symptomatic improvement but with substantial between-study variability. Corneal fluorescein staining decreased by MD = -1.04 (95% CI, -1.23 to -0.84; p < 0.001; I² = 0%), supporting epithelial recovery. No serious treatment-related adverse events were reported; however, safety reporting was heterogeneous and follow-up durations were limited. CONCLUSION: Stem cell and stem cell-derived therapies are associated with significant improvements in both objective and subjective outcomes in DED and demonstrate a favorable short-term safety profile. Nevertheless, heterogeneity in cell source, delivery route, dosage, and study design limits generalizability. Larger, rigorously designed randomized trials with standardized protocols and longer follow-up are required to confirm efficacy and establish long-term safety.
Stem cell-driven biomedical technologies for tooth regeneration: engineering scaffolds, organoid models, and molecular targeted strategies.
Jin Z, Yang B, Zhang S … +7 more , Liu Z, Wang Y, Lin A, Yang K, Yu M, Tian W, Huo F
Stem Cell Res Ther · 2026 Apr · PMID 42063187 · Full text
Tooth loss remains a major unmet clinical challenge, and current prosthetic approaches cannot restore the biological complexity, sensory function, or regenerative capacity of natural teeth. Recent progress in stem cell b...
Tooth loss remains a major unmet clinical challenge, and current prosthetic approaches cannot restore the biological complexity, sensory function, or regenerative capacity of natural teeth. Recent progress in stem cell biology, developmental engineering, and regenerative biomaterials has opened new possibilities for biological tooth regeneration. This review integrates advances across three major research domains that together define the current landscape of translational regenerative dentistry. First, we discuss stem cell-based, scaffold-guided strategies for tooth regeneration. These approaches combine dental and nondental stem cells, including DPSCs, SCAPs, PDLSCs, SHED, and iPSC-derived lineages, with bioactive materials such as HA/TCP ceramics, dentin-derived extracellular matrix scaffolds, and natural or synthetic polymers to promote odontogenic differentiation, vascularization, and periodontal attachment. Second, we summarize emerging tooth organoid and bioengineered tooth germ technologies that recapitulate epithelial-mesenchymal interactions and enable controlled reconstruction of dentin-pulp and periodontal compartments for modeling human odontogenesis. Third, we highlight molecular regulation-driven therapeutic strategies, focusing on the modulation of Wnt, BMP, FGF, TGF-β, and USAG-1 pathways to stimulate endogenous tooth regeneration and correct developmental defects. Despite marked progress, challenges remain, including stable neurovascular integration, optimization of stem cell-material crosstalk, precise control of spatiotemporal signaling, and long-term functional stability in vivo. Finally, we outline future directions involving smart biomaterials, gene- and protein-based molecular targeting, organoid-guided regeneration, and iPSC-enabled personalized therapies, which may further accelerate the clinical translation of stem cell-based tooth regeneration.
CAR-T cells targeting fibroblast activation protein eliminate pathological fibroblasts and preserve cardiac function in a Duchenne Muscular Dystrophy murine model.
Marigny C, Revet G, Berger A … +19 more , Boulch M, Mougenot N, Li Z, Corre B, Lemaitre M, Bois A, Castelli C, Collombat V, Parlakian A, Perier MC, Bot A, Epstein JA, Lafuste P, Hagege A, Aghajanian H, Cochain C, Bousso P, Agbulut O, Menasché P
Stem Cell Res Ther · 2026 Apr · PMID 42063173 · Full text
BACKGROUND: Chimeric Antigen Receptor (CAR)-T cells therapy has revolutionized the treatment of hematological cancers and are currently redirected towards non-malignant diseases. If correction of the gene defect remains...
BACKGROUND: Chimeric Antigen Receptor (CAR)-T cells therapy has revolutionized the treatment of hematological cancers and are currently redirected towards non-malignant diseases. If correction of the gene defect remains the cornerstone of the treatment of Duchenne Muscular Dystrophy (DMD), the disease-associated fibrosis can limit its efficacy. We thus assessed the effects of eliminating cardiac fibrosis of DMD by CAR-T cells targeting Fibroblast Activation Protein (FAP), a protein strongly expressed by activated fibroblasts. METHODS: In vitro CAR-T cells expressing both FAP and a green fluorescent probe (GFP) were first co-cultured with FAP + of FAP- target cells to check for FAP-expressing lymphocyte activation. Then, anti-FAP CAR-T cells were intravenously delivered in a dystrophic murine model (D2.mdx), following lymphodepletion, to investigate the kinetics, biodistribution, cardiac functional and anti-fibrotic effects of anti-FAP CAR-T cells compared with control lymphocytes engineered to only express GFP. The mechanism of action at a cellular level was assessed by single-cell RNA-sequencing of harvested hearts. RESULTS: In vitro anti-FAP CAR-T cells were successfully activated when co-cultured with FAP + target cells. In a dystrophic murine model (D2.mdx), anti-FAP CAR-T cells, intravenously delivered following lymphodepletion, homed to the heart and skeletal muscles, where they decreased FAP and fibrosis-associated genes. Single-cell RNA-sequencing linked these changes to a decrease in a definite cluster of fibrogenic fibroblasts. Concomitantly, anti-FAP CAR-T cells improved cardiac function compared to control mice injected with GFP-transduced T lymphocytes or bovine serum albumin used as negative controls. CONCLUSIONS: These results suggest that anti-FAP CAR-T cells could be efficient for mitigating fibrosis and thus complement gene therapy of DMD. More generally, their therapeutic benefits pave the way for potential applications extending to other fibrosis-associated diseases.
Functional development of photoreceptors in human retinal organoids.
Zhang Y, Du M, Wang YH … +5 more , Li M, Jin K, Pan D, Zhang X, Jin ZB
Stem Cell Res Ther · 2026 Apr · PMID 42063112 · Full text
BACKGROUND: Retinal organoids (ROs) derived from human pluripotent stem cells are crucial for modeling retinal development and disease. However, the functional electrophysiological maturation of photoreceptors within ROs...
BACKGROUND: Retinal organoids (ROs) derived from human pluripotent stem cells are crucial for modeling retinal development and disease. However, the functional electrophysiological maturation of photoreceptors within ROs remains poorly characterized. This study aimed to define the functional maturation timeline of photoreceptors in human embryonic stem cell (hESC)-derived ROs. METHODS: H9 hESC-derived ROs which included a CRX-tdTomato reporter line for specific photoreceptor identification were utilized. An integrated approach of RNA-sequencing analysis, immunofluorescence staining, and whole-cell patch-clamp recordings was employed to systematically assess photoreceptor maturation over 300 days of differentiation. RESULTS: Transcriptional and protein analysis revealed progressive upregulation of key ion channels. Patch-clamp recordings demonstrated stage-dependent maturation of membrane properties, which stabilized by D120-125. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated currents (I) increased progressively, peaking at D240, with amplitudes comparable to mature primate photoreceptors. Voltage-gated sodium (Nav) currents also showed significant developmental upregulation, reaching a maximum, stable plateau from D210-215 onward. Pharmacological blockade confirmed the identity of HCN and Nav currents. Critically, the capacity for action potential (AP) generation increased developmentally, with the proportion of photoreceptors capable of firing APs rising from 16.7% at D90-95 to a peak of 90.2% by D240-245. CONCLUSIONS: This study defines a comprehensive electrophysiological maturation timeline for photoreceptors in human ROs and establishes D240 as a key benchmark for functional maturity, characterized by peak I currents and AP generation capacity equivalent to mature native photoreceptors. These findings provide essential physiological criteria for standardizing RO quality control, enhancing their utility for modeling retinal degenerative diseases and developing cell replacement therapies.
Multi-armored mesenchymal stem cells potentiate antitumor immunity to combat ovarian cancer.
Cao M, Tang Y, Li Y … +8 more , Li J, Shen M, Hu L, Zhang Y, Li D, Wang D, Mao J, Shen J
Stem Cell Res Ther · 2026 Apr · PMID 42057205 · Full text
BACKGROUND: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies often resistant to immune checkpoint blockade (ICB) due to poor infiltration of cytotoxic CD8⁺ T cells and type 1 conventional dendr...
BACKGROUND: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies often resistant to immune checkpoint blockade (ICB) due to poor infiltration of cytotoxic CD8⁺ T cells and type 1 conventional dendritic cells (cDC1s) into the tumor microenvironment (TME). To overcome this, we engineered magnetic resonance imaging (MRI)-visible mesenchymal stem cells (MSCs) to co-express interleukin-15 (IL-15) for T-cell activation and XC motif chemokine ligand 1 (XCL1) for cDC1 recruitment, aiming to remodel the TME and enhance therapeutic outcomes. METHODS: MSCs were engineered via lentiviral transduction to stably express Il15, Xcl1, and a ferritin reporter for MRI tracking. In vitro validation included assays for gene expression, cytokine secretion, T-cell proliferation, and DC migration. Therapeutic efficacy was evaluated in subcutaneous (ID8) and disseminated (intraperitoneal FLUC-eGFP-ID8 and intra-omental FLUC-eGFP-OVHM) murine OC models. Mice received peritumoral (subcutaneous model) or intraperitoneal (disseminated models) injections of engineered MSCs (1×10 cells). Anti-PD-1 antibody (10 mg/kg, twice weekly) was administered intraperitoneally in disseminated models. Tumor progression was monitored by MRI, bioluminescence imaging, and survival analysis. Immune cell infiltration and phenotypes were assessed using flow cytometry, qPCR, immunofluorescence, and immunohistochemistry. RESULTS: Engineered MSCs sustainably secreted IL‑15 and XCL1, enhancing T cell proliferation and cDC1 migration in vitro. In vivo MRI confirmed efficient MSCs homing to subcutaneous tumors, suppressing tumor growth. In disseminated models, multi-armored MSC therapy inhibited tumor progression and prolonged survival, with combination therapy achieving superior outcomes. Mechanistically, this treatment drove a robust infiltration of CD8⁺ T cells and cDC1s into the TME. Flow cytometry revealed a beneficial shift in the CD8⁺ T-cell compartment toward progenitor-like, proliferative, and effector phenotypes. Furthermore, tumor-infiltrating cDC1s displayed elevated expression of co-stimulatory molecules CD80 and CD86, indicating enhanced activation. CONCLUSIONS: MRI-visible MSCs co-expressing IL-15 and XCL1 effectively target ovarian tumors and remodel the immune microenvironment to foster potent anti-tumor immunity. By recruiting activated cDC1s and promoting durable, functional CD8⁺ T-cell responses, these multi-armored MSCs synergize with ICB to overcome therapeutic resistance. This cellular immunotherapy represents a promising strategy for ICB-resistant OC and warrants clinical translation.
Exosomes derived from BMSCs regulate macrophage M1/M2 polarization and promoting tendon-bone healing through circRNA1052.
Wang G, Xu J, Chen Z … +10 more , Wang Z, Lin Y, Xu X, Lu Q, Xu Q, Sun Y, Chen L, Xu L, Li X, Wu F
Stem Cell Res Ther · 2026 Apr · PMID 42057204 · Full text
BACKGROUND: The high retear rate post tendon-bone reconstructive surgery is attributed to scar tissue replacing fibrocartilage, which compromises mechanical properties. Macrophages play a pivotal role in this process. Bo...
BACKGROUND: The high retear rate post tendon-bone reconstructive surgery is attributed to scar tissue replacing fibrocartilage, which compromises mechanical properties. Macrophages play a pivotal role in this process. Bone marrow mesenchymal stem cells-derived exosome (BMSCs-Exo) have emerged as a promising biological therapeutic approach. However, their role and underlying mechanisms in regulating macrophage polarization and tendon-bone healing require further investigation. METHODS: Primary macrophages were cultured, and a rat Achilles tendon-calcaneus reconstruction model was established, followed by BMSCs-Exo treatment. Exosome diameter was analyzed by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Macrophage polarization was assessed via flow cytometry and immunofluorescence. ELISA measured cytokine levels, and immunohistochemistry evaluated molecular expression and distribution. Apoptosis levels were analyzed using TUNEL staining, and HE as well as Safranin O-Fast Green staining were utilized to examine tissue morphology and fibrocartilage regeneration at the tendon-bone junction. Biomechanical testing was used to assess joint stability. Western blot assessed molecular expression, while circRNA-seq was conducted to explore the impact of BMSCs-Exo on circRNA expression profiles in tendon-bone junction macrophages. qRT-PCR quantified circRNA and linear RNA levels, and fluorescence in situ hybridization (FISH) was used to observe circRNA expression and localization. RESULTS: We isolated BMSCs-Exo and discovered its ability to promote macrophage polarization from M1 to M2 both in vitro and in vivo. This polarization was accompanied by a decrease in pro-inflammatory cytokines IL-1β and IL-12, and an increase in anti-inflammatory cytokines TGF-β1 and IL-10. Additionally, BMSCs-Exo significantly enhanced tendon-bone healing, improved the tissue morphology at the tendon-bone junction, increased chondrocyte and fibrocartilage formation, upregulated the expression of collagen I, Aggrecan, and collagen II, improved joint stability. However, macrophage depletion using Clodronate liposomes (CL) effectively inhibited the therapeutic effects of BMSCs-Exo. Mechanistic studies revealed that BMSCs-Exo transfers circRNA1052 to macrophages, driving their polarization from M1 to M2, thereby mitigating early inflammatory responses and enhancing tissue repair during later stages, ultimately facilitating tendon-bone healing. Furthermore, downregulation of circRNA1052 expression attenuated the beneficial effects of BMSCs-Exo. CONCLUSIONS: BMSCs-Exo transfer circRNA1052 to macrophages, suppressing their pro-inflammatory phenotype and promoting polarization toward the tissue-repairing M2 phenotype. This process enhances fibrocartilage formation, improves tissue morphology, and accelerates tendon-bone healing.
Randomized clinical trial comparing intra-articular injection of bone marrow aspirate clot and bone marrow aspirate concentrate in grade 3 and 4 knee osteoarthritis.
Lana JF, Pires L, Macedo A … +7 more , Mainine S, Mosaner T, de Moraes Ferreira Jorge D, Azzini G, da Fonseca LF, Tambeli CH, de Andrade MAP
Stem Cell Res Ther · 2026 Apr · PMID 42057095 · Full text
Knee osteoarthritis (KOA) is a degenerative joint condition characterized by progressive cartilage deterioration and chronic pain, leading to functional impairment. Bone marrow-derived orthobiologics, such as bone marrow...
Knee osteoarthritis (KOA) is a degenerative joint condition characterized by progressive cartilage deterioration and chronic pain, leading to functional impairment. Bone marrow-derived orthobiologics, such as bone marrow aspirate clot (BMA-clot) and bone marrow aspirate concentrate (BMAC), have emerged as promising regenerative therapies. Despite their growing clinical use, no randomized clinical trials to date have directly compared the efficacy and safety of these two approaches in patients with KOA, leaving a gap in the current evidence base. This study aimed to compare the efficacy and safety of intra-articularBMA-clot and BMAC in patients with moderate to severe KOA over a 12-month follow-up period. In this prospective, randomized, double-blind clinical trial, patients aged 50-80 years with Kellgren-Lawrence grade 3-4 KOA were enrolled. Participants received thr ee monthly intra-articular injections of eitherBMA-clot or BMAC. The primary outcome was functional improvement assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included pain reduction (Visual Analog Scale) and quality of life (Short Form-36, SF-36). Adverse events were monitored, and data were analysed using mixed-effectsmodels. Both treatments resulted in significant improvements in pain, function, and quality of life throughout the 12-month period. Clinical outcomes between the BMA-clot and BMAC groups were not statistically different. The incidence of adverse events was low, with no serious complications observed. Intra-articular administration of BMA-clot and BMAC appears to be safe and effective for the management of moderate to severe KOA, providing sustained symptom relief and functional gains over a 12-month period. Given its simpler preparation and lower cost, BMA-clot may represent a more accessible therapeutic option in clinical settings.
Macrophage autophagy-dependent M2 polarization mediates the protective effect of ADSC-conditioned medium against acute lung injury.
Li J, Yang F, Ren Z … +3 more , Zhang C, Xing M, Jiao Z
Stem Cell Res Ther · 2026 Apr · PMID 42050662 · Full text
BACKGROUND: Adipose-derived mesenchymal stem cell conditioned medium (ADSC-CM) has emerged as a promising cell-free therapeutic strategy for acute lung injury (ALI). ADSC-CM's anti-inflammatory effect is closely related...
BACKGROUND: Adipose-derived mesenchymal stem cell conditioned medium (ADSC-CM) has emerged as a promising cell-free therapeutic strategy for acute lung injury (ALI). ADSC-CM's anti-inflammatory effect is closely related to its ability to regulate alveolar macrophage polarization. Furthermore, autophagy in macrophages is considered to be related to the regulation of polarization. However, the specific role and mechanisms by which ADSC-CM coordinates autophagy to guide macrophage polarization are not yet fully clear and urgently require further research. METHODS: We established an in vivo rat model of LPS-induced ALI to evaluate the ameliorative effects of ADSC-CM. Concurrently, an in vitro model utilizing NR8383 alveolar macrophages was employed to investigate the underlying mechanisms. A comprehensive suite of techniques, including ELISA, flow cytometry, immunohistochemistry, Western blot, and RT-qPCR, was applied for analysis. RESULT: In in vivo experiments, ADSC-CM treatment significantly alleviated LPS-induced pneumonia. In vitro experiments revealed that ADSC-CM enhanced the autophagic flux in NR8383 cells and effectively counteracted the promotion of LPS-driven M1 pro-inflammatory phenotypes, while inducing a shift toward M2 anti-inflammatory phenotypes. This beneficial polarization was proven to be dependent on autophagy, as it was significantly reduced when autophagy was inhibited. Mechanistically, autophagy mediated by ADSC-CM was shown to regulate the STAT1/STAT6 signaling pathway and influence HIF-1α expression. CONCLUSION: Our research results indicate that ADSC-CM alleviates ALI by targeting alveolar macrophages. Its protective mechanism involves enhancing autophagy activity, thereby promoting the polarization of macrophages towards the M2 phenotype through the regulation of STAT1/STAT6 and HIF-1α pathways. This study reveals the immunomodulatory role of ADSC-CM dependent on autophagy, highlighting its potential as an acellular therapeutic strategy for treating ALI.
Advanced regenerative solutions in diabetic foot ulcer therapy: delivery of mesenchymal stem cells in injectable hydrogels.
Sadrzadeh SA, Ranjbar M, Meybodi MJE … +4 more , Khorram Y, Sani M, Latifi M, Sani F
Stem Cell Res Ther · 2026 Apr · PMID 42045987 · Full text
Diabetic foot ulcers (DFUs) are a severe complication of diabetes characterized by impaired healing driven by oxidative stress, chronic inflammation, reduced angiogenesis, and neuropathy, leading to high risks of infecti...
Diabetic foot ulcers (DFUs) are a severe complication of diabetes characterized by impaired healing driven by oxidative stress, chronic inflammation, reduced angiogenesis, and neuropathy, leading to high risks of infection and amputation. Current therapies remain insufficient, necessitating advanced regenerative approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential through immunomodulation, angiogenesis, and extracellular matrix remodeling; however, their clinical application is limited by poor survival and retention, as well as potential safety concerns. Increasing evidence indicates that MSC-derived exosomes play a central role in mediating these therapeutic effects via paracrine signaling, delivering bioactive cargos such as microRNAs, proteins, and cytokines that regulate immune responses, angiogenesis, and tissue regeneration with lower immunogenicity and improved stability compared to cell-based therapies. Injectable hydrogels have emerged as biomimetic platforms that not only enhance MSC viability and retention but also provide an optimal delivery system for exosomes by protecting them from degradation and enabling sustained, localized release within the wound microenvironment. The integration of MSC-derived exosomes with hydrogel systems represents a synergistic strategy that simultaneously addresses multiple pathological barriers in DFUs, including inflammation, oxidative stress, and impaired vascularization. This review highlights recent advances in hydrogel-based delivery systems for MSCs and, importantly, MSC-derived exosomes, with a particular emphasis on their combined therapeutic potential in diabetic wound healing. Furthermore, emerging smart and stimuli-responsive hydrogels are discussed as next-generation platforms for optimizing exosome delivery and improving clinical outcomes in DFUs.
Urine-derived stem cells in kidney disease: progress, challenges, and future directions.
Atay JCL, Boysen AT, Nørregaard R
Stem Cell Res Ther · 2026 Apr · PMID 42036721 · Full text
Chronic kidney disease (CKD) is a major global health burden with limited treatment options that address the underlying causes of fibrosis or promote regeneration. Urine-derived stem cells (USCs) have emerged as a promis...
Chronic kidney disease (CKD) is a major global health burden with limited treatment options that address the underlying causes of fibrosis or promote regeneration. Urine-derived stem cells (USCs) have emerged as a promising tool in regenerative nephrology, offering a non-invasive and accessible source of multipotent cells with therapeutic potential. Sharing key properties with mesenchymal stem cells, USCs demonstrate paracrine activity, immunomodulation, and efficient extracellular vesicle (EV) production, and have shown anti-fibrotic, anti-inflammatory, and pro-regenerative effects in preclinical models of acute and chronic kidney injury. Recent advances in biomaterials and delivery technologies, including scaffold-free cell sheets and engineered EVs, have further enhanced the potential of USC-based therapies. However, challenges remain, particularly regarding functional integration, delivery optimization, and donor variability. This review summarizes the current progress in USC-based kidney therapy, identifies key limitations, and outlines future directions to support the translation of USC-based interventions into clinical practice.
Apelin-13 enhances BMSCs osteogenic differentiation and bone regeneration under hypoxia via upregulation of Ibsp.
Tao J, Qiu X, Fu D … +6 more , Wu S, Wang Z, Zhang C, Hong M, Duan S, Jing W
Stem Cell Res Ther · 2026 Apr · PMID 42036716 · Full text
BACKGROUND: Apelin-13 plays a critical role in promoting angiogenesis and regulating cellular metabolism. However, the short half-life of Apelin-13 in vivo limits its further applications. Stem cell transplantation has b...
BACKGROUND: Apelin-13 plays a critical role in promoting angiogenesis and regulating cellular metabolism. However, the short half-life of Apelin-13 in vivo limits its further applications. Stem cell transplantation has been widely applied in tissue regeneration, but the low survival rate of transplanted stem cells in vivo restricts its therapeutic efficacy. This study aims to combine Apelin-13 with stem cell transplantation to enhance the survival rate of transplanted stem cells and promote bone regeneration. METHODS: In this study, BMSCs and HUVEC were pretreated with different concentrations of Apelin-13 to investigate its effects on their proliferation, differentiation capacities under hypoxic conditions (1% O₂). A rat mandibular bone defect model was employed to evaluate the promotive effects of Apelin-13-BMSCs and Apelin-13-HUVEC transplantation on bone regeneration, and RNA sequencing together with a rat closed femoral fracture model was further used to explore the potential mechanisms by which Apelin-13 enhances BMSC proliferation and differentiation. RESULTS: Apelin-13 enhances the proliferative and differentiation capacities of BMSCs and HUVEC under hypoxic conditions, reduces apoptosis, and exerts these promotive effects in a dose-dependent manner. BMSCs pretreated with Apelin-13 markedly facilitate the repair of rat mandibular bone defects and the healing of femoral fractures. Mechanistically, Apelin-13 promotes proliferation and osteogenic differentiation by upregulating Ibsp expression in BMSCs. CONCLUSION: BMSCs pretreated with Apelin-13 exhibited favorable regenerative and differentiation capacities in both in vitro and in vivo experiments, providing a potential strategy to address the challenges of low survival rates and stemness decline following stem cell transplantation in vivo.
Lyophilized mesenchymal stromal cell-derived extracellular vesicles for the oral treatment of inflammatory bowel disease: a novel cell-free therapeutic strategy.
Yang S, Chen S, Zhuang W … +5 more , Wang Q, Xu Y, Zhan T, Huang W, Tan Y
Stem Cell Res Ther · 2026 Apr · PMID 42036713 · Full text
BACKGROUND: Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. Current standard treatments, in...
BACKGROUND: Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn's disease (CD), is a chronic and relapsing inflammatory disorder of the gastrointestinal tract. Current standard treatments, including aminosalicylates, corticosteroids, immunomodulators, and biologic therapies, can induce and maintain remission; however, a considerable proportion of patients show limited responsiveness or experience adverse effects. This highlights the urgent need for safer and more effective therapeutic alternatives. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising cell-free therapeutic modality owing to their immunomodulatory and reparative capabilities. These vesicles replicate many of the therapeutic benefits of mesenchymal stromal cells (MSCs) while avoiding the risks associated with conventional cell-based treatments. Nevertheless, clinical translation of MSC-EVs for IBD management remains constrained by issues such as limited storage stability and invasive delivery routes. METHODS: Extracellular vesicles (EVs) were isolated from the culture supernatant of human umbilical cord-derived MSCs via tangential flow filtration (TFF) followed by ultracentrifugation, and were characterized using transmission electron microscopy, western blotting, and nanoflow cytometry. To enhance their stability, MSC-EVs were lyophilized with trehalose and mannitol serving as cryoprotectants. The lyophilized powder was subsequently encapsulated in enteric-coated capsules for oral administration. The therapeutic efficacy of this formulation was evaluated in a dextran sulfate sodium (DSS)-induced rat colitis model. Disease activity was recorded daily, and post-experimental analyses included histopathology, immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and serum biochemistry to evaluate hepatorenal function. RESULTS: A robust lyophilization protocol was successfully established to enhance MSC-EV stability, along with an innovative oral delivery system for IBD therapy. In DSS-induced colitis rats, lyophilized MSC-EVs markedly alleviated disease severity, as indicated by a reduced disease activity index (DAI), preserved colon length, and improved histological architecture. MSC-EV administration restored intestinal barrier integrity, modulated cytokine expression profiles, mitigated systemic inflammation, and improved hepatic and renal function. CONCLUSIONS: This study demonstrated the therapeutic efficacy of a lyophilized, orally administered MSC-EV formulation in experimental colitis. This approach not only enhances vesicle stability and simplifies storage but also provides a non-invasive, patient-friendly route of administration. These findings underscore the strong translational potential of lyophilized MSC-EVs as a practical and effective cell-free therapeutic strategy for IBD.
Induction of fibrosis in human kidney organoids delineates mechanisms and therapeutic targets of fibrotic kidney disease.
Doeser MC, Raimann J, Beuke M … +6 more , Kilcan Z, Menke AF, Klinkhammer BM, Boor P, Schöler HR, Pavenstädt H
Stem Cell Res Ther · 2026 Apr · PMID 42036700 · Full text
BACKGROUND: Developing regenerative therapies to restore kidney function in patients with progressive renal disease represents a major challenge for modern molecular nephrology. Kidney organoids, three-dimensional kidney...
BACKGROUND: Developing regenerative therapies to restore kidney function in patients with progressive renal disease represents a major challenge for modern molecular nephrology. Kidney organoids, three-dimensional kidney-like structures, which can now be generated by the directed differentiation of human pluripotent stem cells, have emerged as a powerful tool to study kidney development, physiology, and mechanisms of renal disease in vitro. Ultimately, kidney organoids may serve as an experimental platform to unravel the pathomechanisms of renal fibrosis and to test regenerative treatment approaches targeting fibrotic kidney diseases. However, the fibrotic phenotype in kidney organoids and its utility as a disease model remain to be fully characterized. METHODS: Three-dimensional self-organizing kidney organoids containing nephrons and stromal cells were exposed to TGF-β1 cytokine to induce fibrotic remodeling. Organoids were analyzed by RNA sequencing and histology. RESULTS: Activation of TGF-β1 signaling in kidney organoids induced hallmarks of human kidney fibrosis, such as tubular atrophy, glomerulosclerosis, and interstitial fibrosis. RNA sequencing highlighted differential regulation of key pathways in kidney fibrosis: epithelial-to-mesenchymal transition, inflammation, metabolism, and JAK/STAT signaling. We identified candidate mediators of kidney fibrosis such as the JAK-STAT downstream target PIM1. Inhibition of PIM1 with the small molecule AZD1208 attenuated fibrosis development in the organoids. CONCLUSIONS: Kidney organoids are an amenable system for modeling kidney fibrosis and may guide therapeutic discovery.
iPSC-derived exosomes promote diabetic wound healing by attenuating inflammatory responses.
Long L, Qiao J, Wang L … +7 more , Wang Y, Xu Y, Chen H, Jin H, He W, Han X, Zhang J
Stem Cell Res Ther · 2026 Apr · PMID 42036682 · Full text
BACKGROUND: Owing to impaired glucose metabolism, the high-glucose microenvironment in diabetic patients disrupts a series of biological reactions that hinder the wound healing process, resulting in a significant cost to...
BACKGROUND: Owing to impaired glucose metabolism, the high-glucose microenvironment in diabetic patients disrupts a series of biological reactions that hinder the wound healing process, resulting in a significant cost to the health care system and an urgent need for new and advanced therapies. METHODS: In this study, induced pluripotent stem cell-derived exosomes (iPSC-Exos) were isolated from iPSC culture supernatant via centrifugation and ultrafiltration. We evaluated the therapeutic effects of iPSC-Exos on diabetic wound healing through two clinically relevant animal models (spontaneous genetic diabetic mouse model and streptozotocin (STZ)-induced diabetic mouse model). iPSC-Exos were topically administered to full-thickness cutaneous wounds in diabetic mice. The therapeutic effects were systematically assessed by measuring wound closure rates, conducting comprehensive histopathological evaluations, and performing quantitative analysis of inflammatory mediators via ELISA. RESULTS: We demonstrated that iPSC-Exos can significantly accelerate diabetic wound healing through two clinically relevant animal models (spontaneous genetic diabetic mouse model and STZ-induced diabetic mouse model) for the first time. The multifaceted therapeutic mechanisms include: (ⅰ) Direct activation of tissue regeneration (promotion of re-epithelialization, tissue remodeling and scar attenuation); (ⅱ) Modulation of the inflammatory microenvironment (promoting macrophage polarization toward anti-inflammatory M2 phenotype/suppressing inflammation). CONCLUSIONS: This dual-animal model approach, which closely recapitulates key pathophysiological features of human diabetic wounds, offers superior clinical translatability compared to single-animal model studies. Our findings not only establish a robust scientific foundation for clinical development of iPSC-Exos therapy, but also present a transformative, cell-free treatment paradigm for chronic diabetic wounds that addresses critical unmet medical needs.
Generation of functional mesothelial cells from human iPSCs that restore peritoneal integrity in experimental peritoneal injury.
Kato T, Yamashita M, Yasuda M … +11 more , Ando Y, Nakatsuka R, Shirouzu Y, Fujioka T, Tsukasaki M, Hattori F, Taniyama Y, Ogata H, Sakashita A, Honda H, Hitomi H
Stem Cell Res Ther · 2026 Apr · PMID 42035221 · Full text
BACKGROUND: Long-term peritoneal injury results in loss of mesothelial integrity and impaired ultrafiltration, limiting the durability of peritoneal dialysis. Because primary human peritoneal mesothelial cells (PMCs) are...
BACKGROUND: Long-term peritoneal injury results in loss of mesothelial integrity and impaired ultrafiltration, limiting the durability of peritoneal dialysis. Because primary human peritoneal mesothelial cells (PMCs) are difficult to obtain and expand, regenerative strategies for restoring peritoneal function have remained limited. METHODS: We developed a protocol to differentiate human induced pluripotent stem cells (iPSCs) into functional peritoneal mesothelial-like cells (iPMCs). The molecular and functional characteristics of iPMCs were evaluated using gene expression analyses and functional assays, including comparison with a mesothelial cell model. The therapeutic effect of iPMCs was evaluated in a methylglyoxal-induced experimental peritoneal injury mouse model. RESULTS: iPMCs exhibited typical cobblestone morphology and expressed key mesothelial markers including CK18, WT1 and MSLN. Transcriptomic analysis demonstrated strong similarity between iPMCs and primary PMCs. In vivo, intraperitoneal administration of iPMCs partially improved peritoneal transport parameters in a mouse model of peritoneal injury. CONCLUSIONS: We successfully generated functional mesothelial cells from human iPSCs that reproduce mesothelial-like functional properties and suggest potential for restoring peritoneal integrity. This study demonstrates the feasibility of iPSC-derived mesothelial cells as a regenerative cell source for peritoneal repair and provides a foundation for future peritoneal regeneration therapy.
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