Stem Cell Res Ther [JOURNAL]
Sun
200 papers
Bioreactor-derived EVs from placental MSCs show context- and donor-specific immunomodulatory trends in human 3D lung inflammatory models.
Soroczynska K, Dlugolecka M, Mačiulaitis J … +7 more , Insodaitė R, Valiukevičius P, Čiapienė I, Kuzaitytė U, Kliucinskas M, Mačiulaitis R, Czystowska-Kuzmicz M
Stem Cell Res Ther · 2026 Jun · PMID 42321932 · Full text
BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have garnered attention as cell-free therapeutics due to their regenerative and immunomodulatory potential. Human placenta-derived st...
BACKGROUND: Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have garnered attention as cell-free therapeutics due to their regenerative and immunomodulatory potential. Human placenta-derived stromal cells (hPSCs) are a particularly promising source owing to their accessibility, scalability, and superior proliferative capacity-yet the functional behavior of their EVs, especially in inflammatory disease contexts, remains poorly defined. This study introduces a novel integrated approach, combining a 3D microcarrier bioreactor for scalable EV production with advanced 3D human airway disease models, to resolve how donor variability and inflammatory context shape the immunomodulatory activity of hPSC-EVs. METHODS: hPSCs were expanded under Good Manufacturing Practice (GMP)-compliant conditions in both conventional 2D cultures and 3D stirred-tank bioreactors using microcarrier technology. EVs were isolated from conditioned media via tangential flow filtration and characterized by fluorescent nanoparticle tracking analysis (fNTA), flow cytometry and protein content. Functional effects of hPSCs and EVs were assessed in PBMC co-cultures and two human 3D airway models-cystic fibrosis (CF) and acute respiratory distress syndrome (ARDS)-based on the Epithelix SmallAir™ platform, integrating primary airway epithelium and macrophages at the air-liquid interface. Inflammation was induced with TNF-α (CF) or LPS (ARDS), and EVs or hPSCs were administered to both apical and basal compartments. RESULTS: 3D culture significantly increased EV yield without compromising quality. A key finding was a substantial donor-dependent variability in both hPSC and EV activity, which translated into distinct, model-specific immunomodulatory profiles. Notably, EV- and hPSC-mediated responses diverged across immune and epithelial compartments, indicating that EVs do not simply recapitulate parental cell function. In the 3D models, despite substantial heterogeneity, induction of IL-10 and Arginase-1 (up to 25-fold) in the macrophage compartment emerged as a consistent trend across experimental conditions. In contrast, parental hPSCs showed broader but less predictable cytokine modulation, including variable TNF-α suppression and context-specific effects across donors. CONCLUSIONS: Our findings demonstrate that hPSC- and EV-mediated immunomodulation is highly context-dependent and cannot be predicted solely from donor identity or culture format. Rather than identifying a single optimal condition, this study highlights the need for larger donor cohorts and functional profiling in advanced human models and supports the use of EVs as distinct, cell-free immunomodulatory entities with compartment-specific activity. Together, this work provides a translational framework linking GMP-compliant EV manufacturing with functionally relevant human disease modeling.
Chronic alcohol exposure induces amyloid-beta deposition and impaired neuronal maturation in human iPSC-derived cortical neurons and cerebral organoids.
Koh Y, Kim JW, Jang Y … +3 more , Han J, Rim YA, Ju JH
Stem Cell Res Ther · 2026 Jun · PMID 42321897 · Full text
BACKGROUND: Alcohol consumption has been associated with an increased dementia risk, including Alzheimer's disease (AD). However, the direct impact on human neuronal systems remains insufficiently characterized. METHODS:...
BACKGROUND: Alcohol consumption has been associated with an increased dementia risk, including Alzheimer's disease (AD). However, the direct impact on human neuronal systems remains insufficiently characterized. METHODS: We used human induced pluripotent stem cells (iPSC)-derived cortical neurons, spheroids, and cerebral organoids exposed to physiologically relevant ethanol concentrations for seven days. We assessed neuronal maturation, dendritic morphology, and electrophysiological activity, alongside molecular and functional markers related to AD pathology. RESULTS: Chronic ethanol exposure impaired cortical neuronal maturation and network activity and reduced dendritic complexity in human iPSC-derived cortical neurons. Notably, ethanol exposure induced an amyloidogenic shift characterized by increased amyloid-beta (Aβ)-related processing. These changes were consistently observed across both 2D cortical neurons and 3D cerebral organoid models. CONCLUSION: Our findings indicate that chronic alcohol exposure disrupts neuronal maturation and promotes Alzheimer's disease-related pathology in human iPSC-derived neuronal models. This study highlights the value of human iPSC-based platforms for investigating the cellular impact of lifestyle-associated risk factors in neurodegenerative disease.
Efficacy and safety of allogeneic umbilical cord blood mononuclear cells therapy in children with autism spectrum disorder and immune dysregulation: a single-center, double-blinded, randomized, placebo-controlled trial.
Zhang Z, Wang G, Han F … +12 more , Zhou H, Liang Y, Zhang L, Pang P, Cao X, Hu P, Yao X, Sun C, Wang J, Shi X, Hu L, Yang G
Stem Cell Res Ther · 2026 Jun · PMID 42321872 · Full text
BACKGROUND: Immune-inflammatory dysregulation is increasingly implicated in the pathogenesis of autism spectrum disorder (ASD). Umbilical cord blood mononuclear cells (UCB-MNCs), with their immunomodulatory effects, repr...
BACKGROUND: Immune-inflammatory dysregulation is increasingly implicated in the pathogenesis of autism spectrum disorder (ASD). Umbilical cord blood mononuclear cells (UCB-MNCs), with their immunomodulatory effects, represent a promising therapeutic avenue by potentially alleviating neuroinflammation. This study aimed to evaluate the safety and efficacy of multiple intravenous infusions of allogeneic UCB-MNCs in children with ASD and peripheral immune dysregulation. METHODS: In this single-center, double-blind, randomized, placebo-controlled trial (RCT), 34 children (aged 3 to 8 years) diagnosed with ASD were randomly assigned to receive intravenous infusion of allogeneic UCB-MNCs (3 × 10⁸ cells per infusion) (n = 17) or placebo (n = 17) four times with 1-week interval, alongside their existing rehabilitation therapy, and followed up for 13 weeks. The primary endpoint were the Total score of the Social Responsiveness Scale-2 (SRS-2). Additional endpoints was changes of the five domains of the SRS-2, the Vineland Adaptive Behavior Scales-3 (Vineland-3), the Childhood Autism Rating Scale (CARS), Aberrant Behavior Checklist (ABC), Swanson, Nolan, and Pelham Rating Scale-IV (SNAP-IV), Self-Rating Anxiety Scale (SAS) and safety. RESULTS: At final follow-up, the UCB-MNCs group demonstrated a significantly greater reduction in the SRS-2 Total scores (LS Mean Difference = - 6.03, 95% confidence interval [CI]: - 11.93 to - 0.14, P = 0.045) and Social Cognition domain (LS Mean Difference = - 9.95, 95% confidence interval [CI]: - 15.90 to - 4.00, P = 0.002) scores compared to the placebo group. No major allogeneic UCB-MNCs transplantation-related adverse events occurred. CONCLUSION: Allogeneic UCB-MNCs transplantation demonstrated preliminary safety and potential efficacy in improving specific aspects of symptoms in children with ASD and peripheral immune dysregulation. Trial registration This study was registered on ChiCTR.org.cn (Identifier: ChiCTR2400082762). Date registered 12 April 2024. https://www.chictr.org.cn/index.html.
CAV1-dependent mitochondrial transfer from hucMSCs reprograms epithelial lipid metabolism to relieve pulmonary fibrosis.
Shao Y, Zhang J, Liu H … +8 more , Wang Y, Liu B, Yuan X, Jiang M, Lv C, Zhang S, Song X, Li H
Stem Cell Res Ther · 2026 Jun · PMID 42321819 · Full text
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by persistent epithelial injury accompanied by mitochondrial dysfunction. Although mesenchymal stem cells (MSCs) can restore epithelial function by donatin...
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by persistent epithelial injury accompanied by mitochondrial dysfunction. Although mesenchymal stem cells (MSCs) can restore epithelial function by donating mitochondria to damaged cells, the molecular mechanisms driving this process remain unclear. In this study, we demonstrate that caveolin-1 (CAV1) enhances mitochondrial transfer from human umbilical-cord-derived MSCs (hucMSCs) to injured epithelial cells. METHODS: In vitro and in vivo bleomycin-induced models were used to evaluate mitochondrial transfer from hucMSCs to alveolar epithelial cells. Confocal microscopy and intravital lung imaging visualized mitochondrial transfer, while flow cytometry quantified transfer efficiency. Proteomic profiling, mitochondrial functional assays, and lipid analyses were conducted to explore CAV1-associated mechanisms and metabolic outcomes. RESULTS: hucMSC treatment restored mitochondrial membrane potential, ATP production, and epithelial cell viability while reducing reactive oxygen species in injured MLE-12 cells. Proteomic analysis showed significant upregulation of CAV1 in hucMSCs cocultured with injured epithelial cells. In the same dataset, differentially expressed proteins were enriched in pathways related to cytoskeletal remodeling and vesicular transport, supporting a role for hucMSC membrane and trafficking dynamics in mitochondrial delivery. Functional validation confirmed that CAV1 overexpression markedly enhanced mitochondrial transfer and restored mitochondrial function, whereas CAV1 knockdown impaired both transfer efficiency and therapeutic outcomes. Mechanistically, transferred mitochondria promoted mitochondria-lipid droplet tethering, boosted fatty acid β-oxidation, and reduced lipid accumulation. CAV1-overexpressing hucMSCs alleviated alveolar epithelial injury and attenuated pulmonary fibrosis. CONCLUSIONS: Our findings identify CAV1 as a crucial mediator of hucMSC-mediated mitochondrial transfer, which enhances epithelial repair through mitochondrial donation and metabolic reprogramming. These insights provide a mechanistic foundation for optimizing stem cell-based therapies in pulmonary fibrosis.
Human adipose-derived mesenchymal stem cells ameliorate Diabetic Kidney Disease by restoring macrophage efferocytosis.
Wu S, Xu W, Yao J … +8 more , Li R, Yang Y, Jin J, Peng X, Liu W, Xu Z, Mi A, Wang H
Stem Cell Res Ther · 2026 Jun · PMID 42316289 · Full text
BACKGROUND: Diabetic Kidney Disease (DKD) is a major complication driven by chronic inflammation and impaired tissue homeostasis. While mesenchymal stem cells (MSCs) show promise, the precise mechanisms by which human ad...
BACKGROUND: Diabetic Kidney Disease (DKD) is a major complication driven by chronic inflammation and impaired tissue homeostasis. While mesenchymal stem cells (MSCs) show promise, the precise mechanisms by which human adipose-derived MSCs (hASCs) modulate macrophage-mediated resolution of inflammation remain to be fully elucidated. METHODS: We integrated single-cell RNA sequencing (scRNA-seq) analysis of human DKD kidneys with in vivo evaluations in db/db mice and in vitro co-culture models. We employed transcriptomic and molecular approaches to systematically investigate how hASCs impact macrophage functional states. RESULTS: scRNA-seq revealed a significant dysregulation of phagocytosis and efferocytosis pathways in human DKD macrophages. In vivo, hASCs effectively homed to injured kidneys, improved renal filtration, and attenuated pathological injury. Rather than a simple binary pro-inflammation to anti-inflammatory switch, hASC treatment restored a comprehensive efferocytic program involving multiple functional stages: chemotaxis (GPR132), recognition/engulfment (PARP9, ELMO1, RAC1), and lysosomal digestion/exhaution and polarisation (LAMP1, LIPA, PPAR-γ, ABCA1). This multi-targeted enhancement was accompanied contributed to the efficient clearance of apoptotic cells, reduced renal oxidative stress, and the mitigation of chronic inflammation. CONCLUSIONS: Our study systematically delineates the therapeutic benefits of hASCs, suggesting the promotion of macrophage efferocytosis as a significant mechanistic pathway by which hASCs exert their therapeutic effects. Specifically, we demonstrate that hASCs positively regulate key molecular signatures across multiple stages of this process - from "find-me" signal (LPC/GPR132) and "eat-me" recognition (PS/ELMO1) to lysosomal digestion (LAMP1) and subsequent exhaustion and polarisation (LIPA/PPAR-γ/ABCA1).
iPSC-derived cardiac organoids for drug cardiotoxicity evaluation and efficacy prediction in myocardial infarction and cardiac hypertrophy models.
Hou C, Zhang Q, Zhang Z … +8 more , Lin X, Pan H, Wang F, Lou J, Miao L, Song B, Wang J, Zhao H
Stem Cell Res Ther · 2026 Jun · PMID 42310800 · Full text
BACKGROUND: Cardiac organoids (COs) derived from induced pluripotent stem cells (iPSCs) constitute a three-dimensional microphysiological system that more faithfully recapitulates the structural and functional complexity...
BACKGROUND: Cardiac organoids (COs) derived from induced pluripotent stem cells (iPSCs) constitute a three-dimensional microphysiological system that more faithfully recapitulates the structural and functional complexity of human heart tissues compared to traditional two-dimensional cultures or animal models. Therefore, it highlights the significance of iPSC-derived COs in providing more precise platform for assessing drug cytotoxicity, cardiac functional toxicity, developmental toxicity, and therapeutic efficacy in disease models. METHODS: Human iPSCs, after generation from somatic cells using reprogramming factors, were differentiated into COs using dynamic culture system. COs were characterized by cell composition, structure, spontaneous beating, electrophysiological properties. Furthermore, drug cytotoxicity was evaluated by assessing cell viability and lactate dehydrogenase release after exposure of COs to doxorubicin. Cardiac functional toxicity was assessed by monitoring changes in beating after exposure to different compounds. In addition, developmental toxicity was tested using thalidomide. Finally, cardioprotective drug efficacy was evaluated based on the construction of myocardial infarction (MI) and cardiac hypertrophy (CH) models. RESULTS: The reprogrammed iPSCs have successfully generated COs with complex structure and function. Myocardial toxicity induced by anthracycline drugs was faithfully reproduced in organoids. This work also examined the effects of isoproterenol, MYK461, E-4031, and nifedipine on cardiac beating. Long-term exposure to thalidomide triggered abnormal atrial-ventricular differentiation in COs. In MI model, cyclosporine A exerted cardioprotective effects by downregulating apoptosis and inflammation. In CH model, on the other hand, apocynin outperformed metoprolol in alleviating Ang II-induced cardiac hypertrophy. CONCLUSIONS: This study establishes an efficient and stable method for generating uniform and functionally mature COs by utilising dynamic culture systems. Also, we proposes a reliable approach for drug-induced cardiotoxicity assessment and efficacy evaluation on the organoid platform, offering a multipurpose and cutting-edge tool for cardiac drug development.
Interleukin-10-engineered mesenchymal stem/stromal cells exhibit robust immunomodulatory effects in vitro and in vivo.
Carneiro DC, Meira CS, Dias RB … +4 more , Rocha VPC, Damasceno PKF, Barbosa JDV, Soares MBP
Stem Cell Res Ther · 2026 Jun · PMID 42310782 · Full text
INTRODUCTION: A dysregulated inflammatory response to infection can lead to sepsis, a leading cause of mortality worldwide, and effective anti-inflammatory therapies remain limited. Mesenchymal stem/stromal cells (MSCs)...
INTRODUCTION: A dysregulated inflammatory response to infection can lead to sepsis, a leading cause of mortality worldwide, and effective anti-inflammatory therapies remain limited. Mesenchymal stem/stromal cells (MSCs) are attractive candidates as immunomodulatory agents. This study evaluated whether genetic modification of MSCs to express interleukin-10 (IL-10), a key anti-inflammatory cytokine, enhances their immunomodulatory effects. METHODS: Bone marrow-derived MSCs from C57Bl/6 mice were genetically engineered by lentiviral transduction to express mouse IL-10 (MSC-IL-10). The immunomodulatory activity in vitro was assessed by co-cultures with macrophages stimulated with LPS and IFN-γ, as well as in Con A-stimulated splenocytes. BALB/c mice subjected to lipopolysaccharide (LPS)-induced endotoxemia were treated with vehicle, dexamethasone, wild-type MSCs (MSC-WT), or MSC-IL-10. Survival, plasma cytokines, leukocyte profiles, CD11b⁺ inflammatory cells, and organ histopathology and biodistribution were evaluated in vivo. RESULTS: MSC-IL-10 maintained the mesenchymal phenotype and multipotent characteristics while exhibiting robust IL-10 expression. In in vitro assays, MSC-IL-10 significantly decreased the production of the cytokines TNF-α, IL-1β, IL-6, IL-12 or Nos2 expression by stimulated macrophages or splenocytes, demonstrating superior immunomodulatory effects compared to MSC-WT. In in vivo mice models, MSC-IL-10 significantly reduced systemic pro-inflammatory cytokines, restored circulating leukocyte counts, and attenuated CD11b⁺ (Mac-1 integrin) inflammatory cell recruitment, surpassing MSC-WT-treated groups. Importantly, MSC-IL-10 mitigated tissue damage mainly to lungs and exhibited biodistribution to liver, lungs and spleen in LPS-challenged mice. CONCLUSIONS: These results support an enhanced immunomodulatory effect of IL-10-expressing MSCs as a promising cell-based therapeutic approach for sepsis and other inflammatory and immune mediated disorders.
An injectable SFMA/HA-E hydrogel for sustained delivery of hucMSC-derived exosomes promotes myocardial repair after infarction.
Deng G, Zhu S, Ouyang Q … +12 more , He X, Ou YS, Su H, Jiang L, Huang J, Long X, Wu M, Li G, Yu C, Lu C, Zhu P, Nasser MI
Stem Cell Res Ther · 2026 Jun · PMID 42304508 · Full text
BACKGROUND: Myocardial infarction (MI) causes permanent loss of cardiomyocytes and heart failure. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSCs-Exos) have shown therapeutic potential. Still, their...
BACKGROUND: Myocardial infarction (MI) causes permanent loss of cardiomyocytes and heart failure. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSCs-Exos) have shown therapeutic potential. Still, their clinical utility is limited by rapid systemic clearance, highlighting the need for a delivery system to achieve sustained release and effect. METHODS: We fabricated an injectable, photopolymerizable hydrogel consisting of silk fibroin methacrylate (SFMA) and epigallocatechin gallate-grafted hyaluronic acid (HA-E) to encapsulate hucMSC-Exos (SFMA/HA-E+Exos). Therapeutic effects were assessed in a rat MI model using echocardiography, histology, and molecular analysis. RESULTS: The SFMA/HA-E hydrogel exhibited favorable mechanical properties, controllable degradation, and sustained exosome release. In vitro, hucMSC-Exos promoted cell survival, migration, and tube formation under hypoxic conditions. In vivo, a single intramyocardial injection of SFMA/HA-E+Exos significantly improved cardiac function compared with the PBS-treated MI group (LVEF: 70.71 ± 3.04% vs. 30.75 ± 3.55%), reduced fibrosis, and suppressed cardiomyocyte apoptosis. The treatment also reinforced angiogenesis, as indicated by increased numbers of CD31⁺ and α-SMA⁺ vessels, induced a pro-reparative immune microenvironment by shifting macrophages polarization towards the M2 phenotype, and up-regulated the gap junction protein Connexin 43. CONCLUSION: The SFMA/HA-E hydrogel-mediated delivery of hucMSC-Exos provides potent dual therapy through structural support and bioactive signaling, inhibiting adverse remodeling and inducing cardiac repair after MI, and represents a potential therapeutic approach for ischemic heart disease.
Identifying NOTCH signaling-specialized hematopoietic supportive subpopulation from mesenchymal stem cells.
Cao Y, He M, Zhang Y … +4 more , Peng X, Zhang Y, Hu L, Cheng T
Stem Cell Res Ther · 2026 Jun · PMID 42304412 · Full text
BACKGROUND: Human umbilical cord mesenchymal stem cells (UC-MSCs) are widely studied as a promising cellular therapy for a variety of diseases due to their accessible sources, less of ethical concerns, and capacities for...
BACKGROUND: Human umbilical cord mesenchymal stem cells (UC-MSCs) are widely studied as a promising cellular therapy for a variety of diseases due to their accessible sources, less of ethical concerns, and capacities for immunomodulation and tissue repair. However, cellular heterogeneity arising during in vitro expansion imposes challenges in quality control for clinical applications and transform, requiring further investigation. METHODS: Two fetal umbilical cords were obtained from Sinogene C&G Stem Cells Co., Ltd. Primary UC-MSCs were isolated and subjected to continuous in vitro passaging culture. The harvested cells were sorted for single-cell RNA sequencing. A total of 78,178 cells and 14 subpopulations were screened for downstream bioinformatic analysis. Experimental validation was performed through both in vitro cell assays and in vivo animal studies. RESULT: Mid-passage UC-MSCs showed more favorable functional performance, based on differential gene expression and functional enrichment analysis. Furthermore, we obtained an optimal subpopulation (C8) during clinical-grade cell culture by holistic evaluation of stemness, hematopoietic support capacity, and immunomodulatory potential. The stemness maintenance of C8 subpopulation was closely associated with NOTCH signaling pathway, as identified by cell-cell communication network analysis. Further analyses established NOTCH2 as the dominant receptor mediating NOTCH signaling in UC-MSCs. Notably, we identified MLPH and LPXN as signature markers specifically enriched in the C8 subpopulation. MLPHLPXN UC-MSCs displayed higher hematopoietic support and immunosuppression capabilities compared to MLPHLPXN UC-MSCs. CONCLUSIONS: Mid-passage UC-MSCs demonstrate favorable characteristics for clinical applications. The UC-MSC subpopulation with high NOTCH signaling activity exhibits enhanced hematopoietic support and immunosuppressive capabilities. MLPH and LPXN serve as ideal markers for isolating this functionally subpopulation.
EphB4/EphrinB2 signaling regulates pericyte-like function of DPSCs in angiogenesis via transcriptional factor SRF.
Lin S, Yang F, Wu Z … +5 more , Zhong J, Zhang Y, Liu J, Kang J, Zhang C
Stem Cell Res Ther · 2026 Jun · PMID 42298719 · Full text
BACKGROUND: During angiogenesis, pericytes (PCs) drive vascular stabilization and maturation, a process largely regulated by the transcription factor serum response factor (SRF). Dental pulp stem cells (DPSCs) possess th...
BACKGROUND: During angiogenesis, pericytes (PCs) drive vascular stabilization and maturation, a process largely regulated by the transcription factor serum response factor (SRF). Dental pulp stem cells (DPSCs) possess the potential to acquire PC-like properties and regulate angiogenesis. While EphB4/EphrinB2 signaling is reported to be involved in DPSC-mediated angiogenesis, its role in modulating PC-like function remains unexplored. Therefore, this study aims to investigate how EphB4/EphrinB2 signaling regulates the PC-like properties of DPSCs. METHODS: DPSCs were transfected with lentivirus to knock down or overexpress EphB4. Cell proliferation was assessed by cell counting kit-8 (CCK-8) assay and Ki-67 staining, and cell motility was evaluated using the Boyden chamber assay. To examine the PC-like function of DPSCs, the expression of contractile markers, including alpha-smooth muscle actin (α-SMA), calponin1, and smooth muscle 22-alpha (SM22-α), was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence staining, along with collagen contraction assay. Transcriptome profiling was performed to explore the potential downstream factor. The association between EphB4/EphrinB2 signaling and SRF was determined by Western blot and further verified using small interfering RNA (siRNA), followed by collagen contraction assay. Functional PC behavior of DPSCs was evaluated in a three-dimensional (3D) spheroid sprouting model with human umbilical vein endothelial cells (HUVECs). RESULTS: EphB4 knockdown in DPSCs suppressed the expression of contractile markers and impaired contractility, whereas its overexpression enhanced both. RNA sequencing results revealed an enrichment of differentially expressed genes (DEGs) involved in smooth muscle contraction and Ephrin pathway after EPHB4 silencing. Gene set enrichment analysis (GSEA) showed significant enrichment of smooth muscle contraction, angiogenesis, and neovascularisation-related genes among downregulated genes in EphB4-deficient DPSCs. Moreover, transcription factor binding site (TFBS) of SRF was significantly downregulated. SRF expression closely correlated with EphB4 levels, and SRF silencing abolished EphB4-induced functional enhancement of DPSCs, suggesting SRF as a downstream effector of EphB4/EphrinB2 signaling. 3D spheroid sprouting assay confirmed that EphB4-deficient and SRF-silenced DPSCs failed to restrain HUVEC sprouting due to the impaired PC-like function of DPSCs. CONCLUSIONS: This study elucidates a novel EphB4/EphrinB2/SRF signaling axis that is pivotal in regulating DPSCs into functional PC-like cells during angiogenesis.
Retraction Note: Exploring the dermatological applications of human mesenchymal stem cell secretome: a comprehensive review.
Zare S, Jafarzadeh A, Zare S … +1 more , Shamloo A
Stem Cell Res Ther · 2026 Jun · PMID 42298702 · Full text
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MSCs/EVs-based therapy targeting DAD: research progress and future perspectives from ARDS and COVID-19 to RP-ILD.
Meng X, Wang L, Tian X
Stem Cell Res Ther · 2026 Jun · PMID 42298693 · Full text
Diffuse alveolar damage (DAD) is the core pathological process of acute lung injury, characterized by dual injury to alveolar epithelial and capillary endothelial cells, initiation of an inflammatory storm, and subsequen...
Diffuse alveolar damage (DAD) is the core pathological process of acute lung injury, characterized by dual injury to alveolar epithelial and capillary endothelial cells, initiation of an inflammatory storm, and subsequent fibrotic remodeling, with persistently high clinical mortality. This pathological change is not restricted to a single disease but widely exists in critical pulmonary disorders such as acute respiratory distress syndrome (ARDS), severe COVID-19, and rapidly progressive interstitial lung disease (RP-ILD), acting as a key driver of disease progression. In recent years, mesenchymal stromal cells (MSCs) and their derived extracellular vesicles (EVs) have become research hotspots for their superior immunomodulatory, anti-apoptotic, tissue-repair, and anti-fibrotic properties. Based on the DAD pathological framework, this article systematically correlates epithelial barrier injury, inflammatory cascade amplification and pulmonary fibrotic remodeling with the therapeutic mechanisms of MSCs and their derived EVs in ARDS, COVID-19 and RP-ILD. It aims to provide a solid basis for the clinical translation of MSCs- and EVs-based therapies and promote their development into a mechanism-driven therapeutic paradigm targeting DAD, with great clinical value and academic innovation.
Optimization of polyethylene glycol-based isolation of exosomes from mesenchymal stem cells for regenerative medicine applications.
Adelipour M, Hwang H, Marzouk RM … +6 more , Gab-Allah MA, Lee GS, Moon JH, Kim KK, Lubman DM, Kim J
Stem Cell Res Ther · 2026 Jun · PMID 42289727 · Full text
BACKGROUND: Mesenchymal stem cells (MSCs) and their derived exosomes have gained significant attention in regenerative medicine due to their unique therapeutic properties, including immunomodulatory and regenerative capa...
BACKGROUND: Mesenchymal stem cells (MSCs) and their derived exosomes have gained significant attention in regenerative medicine due to their unique therapeutic properties, including immunomodulatory and regenerative capabilities. However, the development of a simple, scalable, and reproducible method for isolating exosomes from MSC-conditioned media remains a challenge. METHODS: We optimized a polyethylene glycol (PEG)-based precipitation method for exosome isolation by initially evaluating three different PEG molecular weights (1140, 3350, and 8000 Da). Protein quantification and nanoparticle tracking analysis (NTA) were performed for all three PEG types to assess yield and particle size. Based on these results, PEG 3350 and PEG 8000 were selected for further characterization by scanning electron microscopy (SEM), size exclusion chromatography (SEC), and Western blotting. Subsequently, proteomic and metabolomic analyses were conducted using exosomes isolated with PEG 3350. For functional assays, HeLa cells were exposed to increasing concentrations of MSC-derived exosomes under either 1% or 10% fetal bovine serum (FBS). Cell viability was evaluated at 24 h and 48 h using the the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. RESULTS: Our results demonstrated that PEG 3350 provided the highest yield and purity of MSC-derived exosomes. The isolated exosomes exhibited an average size below 200 nm, as confirmed by SEM and NTA. Western blotting validated the presence of exosome-specific markers CD63, CD9, and LGALS3BP, while liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified 357 proteins and 1,085 metabolites, confirming the molecular integrity of the exosomes. Additionally, SEC analysis revealed that repeated PEG-based enrichment cycles effectively improved exosome purity by removing non-vesicular contaminants. Functionally, exosomes isolated with PEG 3350 exhibited no cytotoxicity in HeLa cells and, at higher concentrations, promoted a condition-dependent increase in cell viability. CONCLUSIONS: This study presents an optimized PEG 3350-based method for exosome isolation, providing a scalable and reproducible approach for obtaining high-purity MSC-derived exosomes. These findings have significant implications for the development of exosome-based therapeutics in regenerative medicine.
Gli1⁺ cell aggregates promote type H vessel formation and orchestrate bone defect regeneration.
Ma C, Gao YR, Wang H … +14 more , Sui BD, Huang SS, Zhang Y, Liu L, Zhang XH, Xing SJ, Li YY, Xiao YH, Zheng YN, Ren LH, Jin Y, Zheng CX, Xu HK, Chen J
Stem Cell Res Ther · 2026 Jun · PMID 42289723 · Full text
BACKGROUND: Rapid and stable regeneration of bone defects remains a pressing clinical challenge. We previously fabricated stem cell aggregates (CA) by mimicking developmental condensation and demonstrated their efficacy...
BACKGROUND: Rapid and stable regeneration of bone defects remains a pressing clinical challenge. We previously fabricated stem cell aggregates (CA) by mimicking developmental condensation and demonstrated their efficacy in promoting bone defect repair. Endogenous Gli1 skeletal stromal/progenitor cells (SSPCs) are a pivotal SSPC subtype known to maintain bone homeostasis and enhance bone regeneration; however, the functional properties and translational potential of CA derived from these cells (Gli1 CA) remain largely elusive. METHODS: Single-cell RNA sequencing was performed to characterize differential gene expression profiles between Gli1 and Gli1 SSPCs. The spatial relationship among Gli1 cells, RUNX2 cells, and type H vessels in vivo was further validated. Gli1-CreER;mT/mG transgenic mice were generated to enable the isolation of Gli1 SSPCs and the subsequent fabrication of Gli1 CA. The pro-angiogenic potential of Gli1 CA was assessed in vitro, and the underlying regulatory mechanisms were further explored. Finally, Gli1 CA were implanted into a mouse femoral defect model, and bone regenerative efficacy was evaluated by micro-CT and immunofluorescence staining. RESULTS: Single-cell RNA sequencing revealed that, compared with Gli1 SSPCs, Gli1 SSPCs highly expressed genes associated with osteogenesis, angiogenesis, and extracellular matrix synthesis. In vivo validation demonstrated robust enrichment of Gli1 cells in the metaphysis; these cells exhibited a tight spatial correlation with the osteogenic master transcription factor RUNX2 and type H vessels. We subsequently sorted Gli1 SSPCs via flow cytometry and fabricated CA, and in vitro analysis confirmed that their expression profiles were consistent with the sequencing data. Functional assays further revealed that Gli1 CA promoted endothelial tube formation through paracrine signaling. Ultimately, Gli1 CA markedly accelerated bone regeneration in a mouse femoral defect model compared with unsorted CA and Gli1⁻ CA, likely by inducing type H vessel formation. CONCLUSIONS: This study not only addresses a critical knowledge gap in Gli1 CA-mediated bone regeneration, but also proposes a novel strategy termed "precision screening of endogenous SSPC subsets coupled with targeted aggregate fabrication". This approach offers a more precise therapeutic direction for the regenerative treatment of bone defects.
A noncanonical neuroligin 3-centered complex promotes functional recovery of spinal cord injury.
Zou W, Chen M, Chen N … +10 more , Chen H, Liang H, Lu X, Xu S, Liu P, Wang Y, Hu L, Liu B, Rong L, Li M
Stem Cell Res Ther · 2026 Jun · PMID 42288926 · Full text
BACKGROUND: While human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold great potential for spinal cord injury (SCI) treatment, their intrinsic mechanisms are not fully understood. Given their multipotency,...
BACKGROUND: While human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) hold great potential for spinal cord injury (SCI) treatment, their intrinsic mechanisms are not fully understood. Given their multipotency, especially their neuronal transdifferentiation potential, we hypothesized that investigating the in situ transcriptional reprogramming of transplanted hUC-MSCs within the spinal cord microenvironment (SCE) could shed light on crucial genes for SCI repair. METHODS: DiD-labeled hUC-MSCs were intrathecally transplanted in rats with or without sub-acute spinal cord bilateral hemisection injury and subsequently retrieved for RNA-seq. Comparative analysis of the transcriptomes of hUC-MSCs and functional screenings in vitro and in vivo, including heterologous synapse formation assay, transplantation of MSCs with gene overexpression or knockdown, AAV-mediated neuron-specific gene expression in SCI rats, behavioral tests, and motor evoked potentials (MEPs) were performed to identify the novel target gene Neuroligin 3 (Nlgn3). Immunoprecipitation followed by mass spectrometry (IP-Mass spec), cell aggregation assay, and immuno-electron microscopy were used to reveal the functional interacting partners of Nlgn3. Moreover, RT-qPCR, western blotting, immunofluorescence staining, and co-IP were used to elucidate the underlying mechanism. RESULTS: Using RNA-seq and functional screening, we identified NLGN3 as a neuronal cell adhesion molecule (CAM) activated by the SCE in transplanted hUC-MSCs to promote therapeutic efficacy. Critically, the neuron-specific restoration of Nlgn3 in the injured spinal cord alone was sufficient to achieve a comparable therapeutic effect. Mechanistically, Nlgn3 recruits the synaptic vesicle proteins Sar1a and Hspa8 to modulate synaptic strength. The combinatorial restoration of Nlgn3 with either Sar1a or Hspa8 synergistically enhanced SCI repair, highlighting the functional importance of this noncanonical Nlgn3-Sar1a-Hspa8 axis. CONCLUSIONS: This work unveils a novel therapeutic role for Nlgn3 in SCI treatment, demonstrating its ability to both enhance MSC transplantation efficacy and directly promote neural circuit reconstruction. We also propose a combinatorial strategy of targeting the noncanonical Nlgn3-centered protein complex. Furthermore, our study provides a valuable framework for uncovering novel therapeutic targets by investigating the transcriptional reprogramming of transplanted MSCs within injury microenvironments.
BDNF secreted by mesenchymal stem cells ameliorates the accelerated meiotic progression in aged mouse oocytes by activating the PI3K/AKT pathway.
Mi X, Zhou J, Chen C … +7 more , Zhou J, Yang Y, Wang H, Jiao X, Qin Y, Chen ZJ, Zhao S
Stem Cell Res Ther · 2026 Jun · PMID 42286606 · Full text
BACKGROUND: Oocyte aneuploidy is a major contributor to age-related fertility decline, but the effective treatments are still unavailable. The spindle assembly checkpoint (SAC), which functions to maintain chromosomal eu...
BACKGROUND: Oocyte aneuploidy is a major contributor to age-related fertility decline, but the effective treatments are still unavailable. The spindle assembly checkpoint (SAC), which functions to maintain chromosomal euploidy in oocytes, may become impaired with aging, manifesting primarily as an aberrant acceleration of meiotic progression. In the present study, we investigated the effects, effective components, and molecular mechanisms of the secretome of mesenchymal stem cells (MSC-sec) in reducing aneuploidy by alleviating the accelerated meiotic progression of aged mouse oocytes. METHODS: MSC-sec was added to oocyte culture medium and its effects on aged oocytes were evaluated through analysis of meiotic process, chromosome alignment, the expression and localization of SAC proteins BubR1 and ZW10. The critical role of the PI3K/AKT pathway was confirmed by application of the inhibitor LY294002. Exogenous brain-derived neurotrophic factor (BDNF) or BDNF neutralizing antibodies were used to identify the effective components of MSC-sec. The in vitro effects of 7,8-dihydroxyflavone (7,8-DHF), a BDNF receptor agonist, were validated through PI3K/AKT and ERK1/2 pathway activity, meiotic progression and aneuploidy assays, while its in vivo effects were assessed by oocyte quality and early embryo development following intraperitoneal injection. RESULTS: MSC-sec could ameliorate age-related accelerated meiotic progression and increase the expression of BubR1 and ZW10 at the kinetochore in mouse oocyte. MSC-sec treatment activates the PI3K/AKT pathway in aged oocytes, and its effect on meiotic progression can be blocked by the PI3K inhibitor LY294002. BDNF is identified as the effective component of MSC-sec in decelerating the meiotic progression. In vitro application of 7,8-DHF ameliorated the accelerated meiotic progression and reduced the aneuploidy rate in aged oocytes, effectively mimicking the effects of BDNF. In vivo administration of 7,8-DHF significantly enhanced oocyte quality and early embryo development in aged mice. CONCLUSIONS: We found that BDNF secreted by MSCs ameliorates the accelerated meiotic progression in aged mouse oocytes by activating the PI3K/AKT pathway, which may be attributed to an improvement in SAC function. Our study elucidates the molecular mechanism and effective component of MSC-sec to alleviate aneuploidy of aged oocytes, providing an experimental foundation for the clinical translation of BDNF or its alternative 7,8-DHF in improving the quality and development potential of oocytes from aged women.
Anti-miR-195-engineered mesenchymal stem cells promote migration, vascularization, and ECM protein expression in vivo.
Moura SR, Cortez MM, Brandão I … +4 more , Alencastre I, Santos SG, Cunha C, Almeida MI
Stem Cell Res Ther · 2026 Jun · PMID 42277931 · Full text
Advanced therapy medicinal products (ATMPs) involving mesenchymal stromal/stem cells (MSCs) have emerged as a promising therapeutic approach for a wide spectrum of diseases, including several musculoskeletal disorders an...
Advanced therapy medicinal products (ATMPs) involving mesenchymal stromal/stem cells (MSCs) have emerged as a promising therapeutic approach for a wide spectrum of diseases, including several musculoskeletal disorders and bone fractures. Despite their potential, clinical translation has often led to inconsistent outcomes and the therapeutic efficacy of unmodified MSCs remains suboptimal. To overcome these challenges, strategies to enhance the functional properties of MSCs are needed. MicroRNAs (miRNAs) are master regulators of gene expression and have emerged as powerful tools for engineering MSCs to enhance their pro-regenerative capacity and potentially improve clinical outcomes. High-throughput RNA sequencing was performed to characterize transcriptional changes induced by anti-miR-195 modulation. Anti-miR-195-modulated MSCs were seeded onto collagen/hydroxyapatite scaffolds and their potential was evaluated in vivo using a heterotopic bone formation mouse model. Histological and molecular analyses were performed at 14 and 28 days post-implantation to assess cell migration, osteogenic marker expression, collagen deposition and vascularization. Anti-miR-195-modulated MSCs displayed transcriptional profiles associated with enhanced migration, invasion, and cell cycle progression, together with reduced senescence, cell death and apoptosis. Expression of the bone mineral density-associated transcript IBSP was significantly increased. In vivo, scaffolds seeded with anti-miR-195-treated MSCs showed increased cell migration at day 14 post-implantation. At day 28 post-implantation, enhanced collagen deposition and increased expression of osteogenic markers, including RUNX2 and SPP1, were observed. In addition, the scaffold area covered by blood vessels and the number of larger vessels were significantly higher in anti-miR-195-MSC scaffolds compared with controls. These findings demonstrate that anti-miR-195 promotes cell migration and vascularization in vivo, supporting miRNA-based engineering as a promising strategy to improve the efficacy of MSC-based ATMPs for musculoskeletal diseases and bone defects.
iMSC-secreted factors preserve renal capillary networks and ameliorate fibrosis by interrupting the macrophage STING/CD8 T cell axis in ischemic kidney disease.
Li M, Zhang Y, He X … +10 more , Liu Z, Li Y, Lu Y, Du L, Cheng X, Wang Y, Jiao Y, Ao Q, Xiao F, Cheng Q
Stem Cell Res Ther · 2026 Jun · PMID 42277882 · Full text
BACKGROUND: Renal fibrosis, the common endpoint of chronic kidney disease, is exacerbated by renal ischemia. While human iPSC-derived MSCs (iMSCs) hold therapeutic promise, their role in modulating the ischemic renal mic...
BACKGROUND: Renal fibrosis, the common endpoint of chronic kidney disease, is exacerbated by renal ischemia. While human iPSC-derived MSCs (iMSCs) hold therapeutic promise, their role in modulating the ischemic renal microenvironment, particularly through macrophage-immune crosstalk, remains unclear. This study assesses whether iMSCs alleviate renal fibrosis by targeting macrophage-STING to restore capillaries. METHODS: The protective effects of iMSC-conditioned medium (iMSC-CM) were assessed in H₂O₂‑induced HK‑2 and HUVEC models using CCK‑8, ROS staining, scratch assay, and tube formation assays. A mouse model of unilateral ischemia‑reperfusion (UIR) was established; mice received intravenous iMSCs or PBS. Kidneys were analyzed by histology, immunohistochemistry, qPCR, and Western blot. Transcriptomic sequencing revealed enrichment of immune-related pathways, including the STING pathway. To validate the role of STING, UIR mice were treated with the STING agonist DMXAA with or without iMSCs, and STING activation was assessed in LPS-stimulated macrophages in vitro. Macrophage polarization was evaluated by F4/80 co‑staining with CD86 (M1) or CD206 (M2). RESULTS: iMSC-CM mitigated H₂O₂-induced damage in HK-2 cells by promoting proliferation, reducing ROS levels, and suppressing fibrosis markers, and it promoted repair and angiogenesis in HUVECs. In vivo, iMSCs homed to injured kidneys, attenuated inflammation and fibrosis, notably reduced capillary rarefaction. Mechanistically, iMSC treatment profoundly inhibited STING activation in renal macrophages. This suppression disrupted a critical inflammatory axis: it reduced macrophage-derived IFN-β, leading to decreased infiltration of cytotoxic CD8⁺ T cells, which are detrimental to vascular endothelial cells. Consequently, the renal capillary network was preserved. Finally, STING agonist treatment abolished the anti-fibrotic benefits of iMSCs. CONCLUSION: Collectively, this work reveals that iMSCs ameliorate renal fibrosis via the macrophage STING/CD8 T cell axis, thereby preserving renal capillaries and highlighting a novel mechanism for iMSC-based therapy.
Integrated single cell and spatial transcriptomics reveals the cellular and molecular mechanisms underlying UCMSCs treatment of ovarian aging in tree shrews.
Tian C, Ye L, Zhu X … +7 more , Chen M, Ye Q, Zhao X, Wang G, Wang J, Xu J, Pan X
Stem Cell Res Ther · 2026 Jun · PMID 42277867 · Full text
BACKGROUND: Ovarian aging reduces fertility and leads to endocrine disorders, umbilical cord mesenchymal stem cells (UCMSCs) therapy has clinical potential, but a deeper understanding of their cellular and molecular regu...
BACKGROUND: Ovarian aging reduces fertility and leads to endocrine disorders, umbilical cord mesenchymal stem cells (UCMSCs) therapy has clinical potential, but a deeper understanding of their cellular and molecular regulatory mechanisms is still required. METHODS: The old female tree shrews were received UCMSCs treatment via tail vein injection, at 1 × 10⁷ cells/kg once daily for 3 days. Ovaries and peripheral blood were collected after UCMSCs therapy 3 months, HE staining was performed to observe the number of follicles, ELISA was used to detect the secretion of sex hormones, immunohistochemical and immunofluorescence staining was used to detect the expression of ovarian aging relative markers, and scRNA-seq and spatial transcriptomics were performed on ovaries to map the cellular spatial atlas, analyze aging-related scores, and reveal their cellular and molecular regulatory mechanisms. RESULTS: UCMSCs increased the number of follicles, boosted the secretion of sex hormones, inhibited the expression of p16, and enhanced proliferation and autophagy in ovarian aging model of tree shrews, but did not fully recover to the level of the young group. Following UCMSCs therapy, the relative abundances of oocytes, theca cells, granulosa cells, perivascular cells, and epithelial cells increased, whereas those of stromal cells decreased, and intercellular communication between oocytes and granulosa, endothelial, and epithelial cells amplified. Within the follicle microenvironment, oocytes reduce genAge scores, and enhance DNA repair capacity. Granulosa cells reduce celluar senescence scores, downregulate CDKN1A, and increase proliferation. Theca cells exhibit enhance DNA repair. Stromal cells exhibit an expanded progenitor pool at the trajectory origin and significantly reduced geneAge and SASP scores. Mechanistically, ubiquitin B (UBB) is involved in positively regulating p53 family protein signaling and is positively correlated with SASP and genAge signatures, UCMSCs therapy significantly downregulated both UBB and p53 expression. CONCLUSION: UCMSCs therapy improves the structure and function of the aged ovary, regulates ovarian microenvironment, with UBB emerging as a potential therapeutic target.
Hematopoietic progenitor cells (HPCs) mobilization following high-intensity interval exercise in cancer patients undergoing bone marrow transplantation: preliminary results from a randomized controlled trial.
Zarekar T, Ahmadizad S, Hajifathali A … +2 more , Roshandel E, Karimi M
Stem Cell Res Ther · 2026 Jun · PMID 42271532 · Full text
BACKGROUND AND OBJECTIVE: Hematopoietic progenitor cells (HPCs) mobilization is essential for successful bone marrow transplantation but may be impaired in cancer patients due to prior treatments. High-intensity interval...
BACKGROUND AND OBJECTIVE: Hematopoietic progenitor cells (HPCs) mobilization is essential for successful bone marrow transplantation but may be impaired in cancer patients due to prior treatments. High-intensity interval exercise (HIIE) has been shown to enhance progenitor cell release in healthy individuals; however, its effects in patients with cancer remain unclear. This study aimed to evaluate the acute effects of HIIE on HPC mobilization in patients with cancer undergoing bone marrow transplantation. METHODS: In this randomized controlled trial (RCT), 20 patients with cancer undergoing bone marrow transplantation were randomly assigned to either an exercise (n = 10) or a control (n = 10) group. To determine peak power, patients in the exercise group performed a graded exercise test. After receiving granulocyte-colony stimulating factor, they performed an HIIE protocol consisting of 12 × 1-min efforts at 100% peak power, followed by 1-min active recovery at 20% peak power. Blood samples were collected before and immediately after exercise and analyzed for catecholamines and CD34 + cells. RESULTS: Data analyses revealed a significant increase in epinephrine, norepinephrine, and CD34 + cells after exercise compared with the control group (p < 0.05). In addition, a positive correlation between epinephrine and CD34 + cells was observed after exercise in the HIIE group. However, CD34 + cells and mononuclear cells did not differ significantly between the two groups (p > 0.05). CONCLUSIONS: HIIE can mobilize HPCs by increasing epinephrine. However, the increased catecholamine levels and CD34 + cells after HIIE did not affect the apheresis products, possibly because of differences in HPCs time courses and homing. CLINICAL TRIAL REGISTRATION: Registration of this trial protocol under the scientific name of "The effect of highintensity interval exercise and training on the mobilization of hematopoietic stem cells in autologous bone marrow transplant patients" has been approved in the Iranian Registry of Clinical Trials on 2023-01-08. The registration reference is IRCT20230101057012N1.
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