Stem Cell Res Ther [JOURNAL]
Sun
200 papers
The effect of cladribine-containing conditioning regimen on the efficacy and safety of allogeneic hematopoietic stem cell transplantation for children with acute lymphoblastic leukemia.
Li X, Hu K, Lin S … +12 more , Que L, Ye Y, Han X, Wang Y, Wu X, Zhan L, Zhou D, Li Y, Zhong D, Fang J, Xu H, Huang K
Stem Cell Res Ther · 2026 Mar · PMID 41851884 · Full text
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for children with refractory, relapsed, or high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens are crit...
BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a curative option for children with refractory, relapsed, or high-risk acute lymphoblastic leukemia (ALL). Conditioning regimens are critical for ensuring engraftment and reducing post-transplantation relapse. Cladribine is a purine nucleoside analogue with antileukemic activity and central nervous system penetration. However, its role in conditioning regimens for pediatric ALL remains insufficiently defined. METHODS: We conducted a retrospective cohort study of 66 pediatric patients with ALL who underwent their first allo-HSCT at Sun Yat-sen Memorial Hospital between August 2018 and December 2023. Patients were stratified according to whether cladribine was incorporated into the conditioning regimen (CLAD + vs. CLAD-). Survival outcomes, relapse incidence, regimen-related toxicity, graft-versus-host disease (GVHD), and post-transplantation complications were compared. Sensitivity analyses were performed by restricting the control group to patients receiving non-total body irradiation, chemotherapy-based conditioning. Competing-risk methods were applied where appropriate. RESULTS: Among the 66 children who underwent allo-HSCT, 38 patients received CLAD+ conditioning and 28 received CLAD- regimens. Conditioning intensity scores were significantly lower in the CLAD+ group (4.0 [3.0, 5.0] vs. 4.5 [4.0, 4.5], p < 0.001). Two-year overall survival or transplantation-related mortality did not differ significantly between the two groups. However, the 2-year relapse-free survival was significantly higher in the CLAD+ group (94.44% vs. 81.16%, p = 0.019), with a significantly lower 2-year cumulative incidence of relapse. These findings remained directionally consistent in sensitivity analyses that accounted for regimen heterogeneity and competing risks. Hematopoietic engraftment, the incidence of acute and chronic GVHD, and major post-transplantation complications were comparable between the two groups, while renal and gastrointestinal toxicities were significantly less frequent in the CLAD+ group. CONCLUSION: Incorporation cladribine into conditioning regimens for pediatric ALL is associated with improved relapse-free survival and significantly lower frequencies of renal and gastrointestinal toxicities, without increasing the risk of transplant-related complications. Given the retrospective design and limited number of events, these promising findings warrant prospective validation in future studies.
A novel OTUD5 variant disrupts neural progenitor cell homeostasis: mechanistic insights from HEK293T cell-based analyses.
Xu N, Wang S, Yang T … +4 more , Yu M, Sun Y, Zhan Y, Yu Y
Stem Cell Res Ther · 2026 Mar · PMID 41851816 · Full text
BACKGROUND: Variants in OTUD5 are associated with neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain unclear. This study aimed to investigate the pathogenicity of a novel OTUD5 variant (c...
BACKGROUND: Variants in OTUD5 are associated with neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain unclear. This study aimed to investigate the pathogenicity of a novel OTUD5 variant (c.697G > A, p.Val233Met) and elucidate its regulatory role in neural progenitor cell (NPC) proliferation and differentiation, thereby uncovering the function of OTUD5 in neurodevelopment. METHODS: The OTUD5 variant was identified in two NDD patients via exome sequencing. Patient-derived induced pluripotent stem cells (iPSCs) and CRISPR/Cas9-corrected isogenic controls were generated. NPC proliferative activity was assessed by Ki67 immunofluorescence staining, cell-cycle distribution was analyzed by flow cytometry, and neuronal differentiation was evaluated by Tuj1/MAP2 immunofluorescence staining. Substrate screening was conducted in HEK293T cells using co-immunoprecipitation (Co-IP) and mass spectrometry. Deubiquitination capacity and protein stability were validated through ubiquitination assays and cycloheximide (CHX) chase experiments. RESULTS: The p.Val233Met variant, located within the catalytic OTU domain, induced a marked conformational alteration in the OTUD5 protein. Functionally, the variant caused aberrant NPC proliferation (1.8-fold increase in Ki67 cells, accompanied by release of G1 arrest) and impaired neuronal differentiation (60% reduction in Tuj cells). Mechanistically, wild-type OTUD5 stabilized GSK3β by removing K48-linked ubiquitin chains, whereas the mutant isoform exhibited diminished deubiquitinase activity, accelerating GSK3β degradation and shortening its half-life by 40%. CONCLUSION: This study establishes a novel disease mechanism whereby OTUD5 mutations disrupt NPC homeostasis through GSK3β destabilization, highlighting the critical role of ubiquitination regulation in neurodevelopment. Our iPSC model provides a platform for testing GSK3β-targeted therapies in OTUD5-related NDDs.
Tanshinone IIA-pretreated mesenchymal stem cells alleviate neuroinflammation in 3×Tg-AD mice via the TREM2/PI3K/Akt pathway.
Wu J, Ge Y, Zhang L … +3 more , Huang J, Huang N, Luo Y
Stem Cell Res Ther · 2026 Mar · PMID 41845487 · Full text
Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our pr...
Neuroinflammation is a key pathogenic factor for neurodegenerative diseases. Mesenchymal stem cell (MSC) transplantation, as a potential strategy for regulating neuroinflammation, has received extensive attention. Our previous research revealed that compared with ordinary MSC, MSC pretreated with tanshinone IIA (TIIA), referred to as TIIA-MSC, exhibited superior anti-neuroinflammatory activity, but the mechanism of action remains unclear. To clarify the underlying mechanism, this study integrated in vitro and in vivo experiments and evaluated the therapeutic effect of TIIA-MSC in a triple-transgenic Alzheimer's disease mouse model (3×Tg-AD mice) and explored its mechanism of action in a lipopolysaccharide (LPS)-induced BV2 microglial cell inflammation model. The results showed that TIIA-MSC could significantly improve the cognitive function of 3×Tg-AD mice, increase brain glucose metabolism levels, promote the recovery of synaptic and mitochondrial structures, and effectively alleviate neuroinflammatory responses. In vitro experiments further verified the superior inhibitory effect of TIIA-MSC on microglial cell activation and proinflammatory factor release. Mechanistic studies have indicated that the triggering receptor expressed on myeloid cells 2 (TREM2) is the key molecule that mediates this process. The knockdown of TREM2 expression significantly weakened the anti-inflammatory effect of TIIA-MSC, suggesting that TREM2 plays a central role in this process. Further analysis revealed that by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway downstream of TREM2, TIIA-MSC may promote the transformation of the functional state of microglia from mainly proinflammatory to having neuroprotective and repair properties. This study systematically revealed the molecular mechanism by which TIIA-MSC regulate microglial cell phenotypic transformation through the TREM2/PI3K/Akt pathway and exert anti-neuroinflammatory effects, providing new ideas and an experimental basis for expanding the application of MSC in the treatment of neurodegenerative diseases.
HMGB1-mediated enhancement of glycolysis activates hepatic stellate cells by inhibiting ferroptosis in alcoholic hepatic fibrosis.
Li Y, Wang Q, Liao Z … +4 more , Wu J, Yu S, Yan H, Xie Z
Stem Cell Res Ther · 2026 Mar · PMID 41840737 · Full text
BACKGROUND: Alcoholic hepatic fibrosis (AHF) ultimately leads to liver cirrhosis and even hepatocellular carcinoma. The aim of this study was to investigate the specific mechanism by which high mobility group protein B1...
BACKGROUND: Alcoholic hepatic fibrosis (AHF) ultimately leads to liver cirrhosis and even hepatocellular carcinoma. The aim of this study was to investigate the specific mechanism by which high mobility group protein B1 (HMGB1) regulated the activation of hepatic stellate cells (HSCs) in AHF. METHODS: CCK-8, EdU staining and flow cytometry assays were utilized to evaluate the viability, proliferation and apoptosis of LX-2 cells stimulated by ethanol. The effect of HMGB1 on cell glycolysis was assessed by cellular energy metabolism assays. The levels of Fe/Fe, ROS, GSH and MDA were detected to evaluate the effect of HMGB1 on ferroptosis. In addition, clinical liver tissue samples and an AHF mouse model were employed to further investigate the effect of HMGB1 on AHF. RESULTS: Ethanol stimulation significantly upregulated HMGB1 and HSC activation markers, enhanced glycolysis, and inhibited ferroptosis in LX-2 cells. Knockdown of HMGB1 suppressed ethanol-induced effects, including HSC activation and glycolysis promotion. However, these effects of HMGB1 knockdown were negated by an oxidative phosphorylation inhibitor. Furthermore, a ferroptosis inducer impeded ethanol-induced HSC activation. Overexpression of HMGB1 decreased the ferroptosis level in ethanol-stimulated LX-2 cells, which was reversed by a glycolysis inhibitor. These in vitro findings demonstrated that upregulated HMGB1 inhibited ferroptosis by enhancing glycolysis, thereby promoting HSC activation. In vivo validation data further confirmed that HMGB1 knockdown inhibited glycolysis, increased ferroptosis level, reduced HSC activation, and alleviated liver fibrosis in AHF mice. Ferroptosis inhibitor counteracted the impacts of HMGB1 knockdown on ferroptosis, HSC activation and liver fibrosis in AHF mice. CONCLUSION: In summary, HMGB1 promoted the metabolism of HSCs towards glycolysis to inhibit ferroptosis, which eventually led to the activation of HSCs and the progression of AHF.
Intervertebral disc progenitor cells: roles in regeneration and disease.
Yan P, He J, Huang Y … +16 more , Lin C, Huang S, Hu O, Lin P, Wang Y, Jin H, Li Y, Qin Q, Wu Y, Wu J, Pu J, Xie Y, Chen L, Lin S, Gan Y, Liu P
Stem Cell Res Ther · 2026 Mar · PMID 41834042 · Full text
Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical...
Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical function of the spine. Regenerative medicine strategies, particularly those harnessing endogenous progenitor cells, offer a promising avenue for achieving biological repair and functional homeostasis. The identification of intervertebral disc progenitor cells (IVD-PCs) has unveiled a potential cellular reservoir for self-repair, given their demonstrated stemness attributes, including clonogenicity and multipotent differentiation. However, the clinical translation of IVD-PCs is significantly hampered by an incomplete understanding of their inherent heterogeneity, hierarchical organization, and, most critically, the dynamic interplay with their unique microenvironment, which dictates their fate decisions. This review synthesizes recent advances in deciphering the molecular signatures and functional plasticity of IVD-PCs. We place a particular emphasis on how key physicochemical, mechanical, and cellular cues within the IVD niche orchestrate progenitor cell behavior-ranging from maintenance and activation to aberrant differentiation-during both homeostasis and degeneration. Furthermore, we propose forward-looking insights to bridge critical knowledge gaps, aiming to propel the development of novel progenitor cell-based therapeutics for IVD degeneration.
Mitochondrial transplant activates Ca/TFAP2A to promote hDPSCs-mediated dentin-pulp regeneration.
Zhan P, Zhang X, Xie Z … +5 more , Chen L, Huang S, Huang Q, Lin Z, Wang R
Stem Cell Res Ther · 2026 Mar · PMID 41827079 · Full text
BACKGROUND: The dentin-pulp complex (DPC) is composed of the odontoblastic layer and associated stromal components. It serves key functions in immunological homeostasis and tissue regeneration of dental tissues. Human de...
BACKGROUND: The dentin-pulp complex (DPC) is composed of the odontoblastic layer and associated stromal components. It serves key functions in immunological homeostasis and tissue regeneration of dental tissues. Human dental pulp stem cells (hDPSCs) have emerged as pivotal cells for DPC regeneration. Current research frontiers primarily focus on developing novel strategies to increase the odontogenic differentiation potential and regenerative efficacy of hDPSCs. This study aims to boost the capacity of hDPSCs to regenerate DPC through mitochondrial transplantation. METHODS: Mitochondria were isolated from donor hDPSCs and transplanted into recipient hDPSCs (Mito-hDPSCs) in the same passage. Subsequently, cell viability and mitochondrial transplantation efficiency were evaluated via CCK-8, β-galactosidase staining, mitochondrial imaging, and flow cytometry. Furthermore, Mito-hDPSCs' metabolic capacity was assessed by mitochondrial membrane potential assays and cellular oxidative phosphorylation assays. Moreover, Alkaline Phosphatase (ALP) activity, Alizarin Red S (ARS) staining, RT-qPCR, and Western blotting (WB) were performed to assess Mito-hDPSC's odontogenic differentiation potential. Moreover, a nude mouse model was used to assess how Mito-hDPSCs induce DPC regeneration in vivo. RNA-Seq analysis was conducted to examine the expression of signaling pathways in Mito-hDPSCs. In addition, ALP, ARS, WB, and Ca fluorescence staining were carried out to analyze the underlying mechanisms between mitochondria and the Ca/Transcription factor activating protein 2α (TFAP2A) signaling axis. RESULTS: The results revealed that mitochondrial transplantation enhanced the viability of Mito-hDPSCs. Furthermore, an increased mitochondrial transplant rate was observed at a recipient-to-donor cell ratio of 1:3. Moreover, Mito-hDPSCs demonstrated increased odontogenic differentiation and formed more dentin-pulp-like tissue in vivo. Ca signaling and odontogenesis were significantly enriched in Mito-hDPSCs. TFAP2A was identified as a key transcription factor in the odontogenic differentiation of Mito-hDPSCs. Knockdown array revealed that mitochondrial transplantation effectively upregulated TFAP2A expression in Mito-hDPSCs. Furthermore, mitochondrial transplantation elevated intracellular Ca concentration, which in turn increased TFAP2A expression. CONCLUSIONS: Mitochondrial transplantation may promote DPC regeneration by regulating the Ca²⁺/TFAP2A signaling axis in Mito-hDPSCs.
Identification of a putative progenitor-like chondrocyte subpopulation in osteoarthritic human cartilage.
Yan W, Chu Z, Qin K … +7 more , Cui C, Yu X, Yan X, Ma C, Sun S, Li W, Liang W
Stem Cell Res Ther · 2026 Mar · PMID 41827033 · Full text
BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown and limited intrinsic repair capacity. Recent single-cell RNA sequencing (scRNA-seq) studies have revealed...
BACKGROUND: Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown and limited intrinsic repair capacity. Recent single-cell RNA sequencing (scRNA-seq) studies have revealed remarkable chondrocyte heterogeneity, identifying multiple functionally distinct subpopulations. Increasing evidence suggests that articular cartilage harbors progenitor-like chondrocytes with regenerative potential. METHODS: Articular chondrocytes were isolated from knee cartilage of six end-stage OA patients and profiled using droplet-based scRNA-seq (~ 14,000 cells). Unsupervised clustering, differential gene expression, and gene ontology (GO) enrichment analyses were performed to define subpopulations and their functional characteristics. Pseudotime trajectory analysis (Monocle) was used to infer lineage relationships and differentiation hierarchies. RESULTS: Twelve transcriptionally distinct chondrocyte clusters were identified, including seven previously described subsets-proliferative, prehypertrophic, hypertrophic, fibrochondrocytic, effector, regulatory, and homeostatic chondrocytes-and three novel ones: NRF2⁺ regulatory chondrocytes enriched in antioxidant pathways, secretory chondrocytes, and progenitor-like chondrocytes(PLCs). Cluster 11 (PLCs) accounted for approximately 2-5% of total chondrocytes and exhibited high expression of stemness-associated genes such as RGS5, PDGFRB, THY1 (CD90), MCAM (CD146), TAGLN, SPARCL1, COL4A1, and ID3. Gene ontology (GO) enrichment revealed activation of developmental and extracellular matrix organization programs, suggesting that these cells are transcriptionally primed for tissue remodelling. Pseudotime mapping positioned PLCs at an early bifurcation upstream of differentiated chondrocyte states, consistent with their progenitor-like role. CONCLUSION: This study delineates the single-cell transcriptomic landscape of OA cartilage and identifies a distinct progenitor-like chondrocyte (PLC) subpopulation with progenitor-associated gene signatures. While functional and spatial validation are still required, the unique molecular features of PLCs raise the hypothesis that they may participate in both intrinsic attempts at cartilage repair and osteoarthritis pathophysiology. These findings provide a conceptual and molecular framework for future studies aimed at isolating PLCs, defining their in vivo behaviour, and exploring their potential as targets for cartilage regeneration or OA modulation.
Editorial Expression of Concern: Co-encapsulation of HNF4α overexpressing UMSCs and human primary hepatocytes ameliorates mouse acute liver failure.
Kong D, Xu H, Chen M … +6 more , Yu Y, Qian Y, Qin T, Tong Y, Xia Q, Hang H
Stem Cell Res Ther · 2026 Mar · PMID 41821118 · Full text
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Intracerebroventricular human mesenchymal stem cells induce MMP9-driven transient inflammation in Alzheimer's disease.
Myeong SH, Lee NK, Lee NH … +5 more , Choi SJ, Son HJ, Chang JW, Kim HJ, Na DL
Stem Cell Res Ther · 2026 Mar · PMID 41814444 · Full text
BACKGROUND: Mesenchymal stem cells (MSCs) are often considered hypoimmunogenic. However, a transient fever observed after intracerebroventricular (ICV) administration in a clinical trial suggests an acute host response....
BACKGROUND: Mesenchymal stem cells (MSCs) are often considered hypoimmunogenic. However, a transient fever observed after intracerebroventricular (ICV) administration in a clinical trial suggests an acute host response. This study examines the mechanisms underlying this reaction, with a focus on MSC migration and the role of matrix metalloproteinase-9 (MMP9). METHODS: We analyzed cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients treated with saline (n = 3) or human MSCs (hMSCs) (n = 6) using an exploratory protease array, followed by enzyme-linked immunosorbent assay (ELISA). The function of MMP9 was examined further through in-vitro migration and lipopolysaccharide (LPS) stimulation assays in MMP9-silenced hMSCs (siMMP9-hMSCs). In-vivo, siMMP9-hMSCs were delivered ICV into 5xFAD mice to evaluate cell distribution and immune responses. RESULTS: CSF protease profiling of AD patients revealed that MSC administration increased MMP9 levels. MMP9 knockdown reduced hMSC migration and attenuated LPS induced cytokine increase in the conditioned media (TNF-α and IL-1β) or in the hMSC lysates (IL-1β, IL-6, and CRP) in-vitro. In 5xFAD mice, siMMP9-hMSCs exhibited altered migration and inflammation signatures, characterized by restricted periventricular distribution accompanied by increased CD45 leukocyte accumulation and caspase-3 activity. Naïve hMSCs, on the other hand, dispersed more broadly. CONCLUSIONS: MMP9 promotes the migration of hMSCs and influences the initial interactions between the host and the graft after ICV delivery. Loss of MMP9 activity limits dispersion and is associated with increased local immune activation. This highlights the importance of MMP9-dependent processes in the early post-transplantation phase. These findings may inform strategies to optimize the safety of central nervous system-directed stem cell therapies. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02054208.
Dual roles of GDNF in enteric glial cell plasticity: direct transdifferentiation via the CaMKII/NeuroD1 pathway and cooperative regulation in a neural stem cell-inducing medium.
Jia W, Yan H, Huang J … +7 more , Liu W, Fu Z, Tian D, Xu W, Chen X, Gao Y, Yu H
Stem Cell Res Ther · 2026 Mar · PMID 41814387 · Full text
BACKGROUND: Hirschsprung disease (HSCR) is a congenital condition featuring aganglionosis in the distal colon, causing functional obstruction. While EGF and bFGF are well-characterized neurogenic factors, the precise mec...
BACKGROUND: Hirschsprung disease (HSCR) is a congenital condition featuring aganglionosis in the distal colon, causing functional obstruction. While EGF and bFGF are well-characterized neurogenic factors, the precise mechanistic role of GDNF in modulating enteric glial cell plasticity remains incompletely understood. METHODS: EGCs were identified via proteomic profiling and immunofluorescence in Ednrb⁻/⁻ mice modeling HSCR. EGC/PK060399egfr and primary EGCs were induced with neural stem cell-inducing medium (NSC-Med). Morphological changes, EdU assay, immunofluorescence, RT‒qPCR, and Western blotting were employed to assess the expression of stemness- and neuron-associated markers. Metabolomic and transcriptomic analyses were performed to evaluate metabolic remodeling and signaling pathways. RESULTS: Following treatment with NSC-Med, immunofluorescence analysis revealed that neurospheres expressed high proportions of Nestin-positive (97.09%), Sox2-positive (50.11%), and p75-positive (77.87%) cells. Metabolomic profiling revealed a significant enhancement of the Warburg effect in the NSC-Med group. Western blot analysis further revealed elevated expression of PKM2, along with significant increases in both extracellular and intracellular lactate levels following NSC-Med treatment. NSC-Med treatment significantly enhanced proliferation, as demonstrated by a 2.3-fold increase in EdU incorporation (P < 0.05). Transcriptomic analysis revealed the activation of the calcium signaling pathway in the GDNF group. Western blotting revealed a significant increase in CaMKII phosphorylation, and treatment with the calcium chelator BAPTA-AM attenuated GDNF-induced NeuroD1 upregulation. CONCLUSION: NSC-Med promotes stem cell-associated features and gene expression in enteric glial cells. GDNF-a key component of NSC-Med-activates a neurogenic cascade via the calcium signaling pathway (CaMKII-NeuroD1 axis), which offers a potential targeted molecular strategy for HSCR therapy.
TSPO governs bone-lipid homeostasis by redirecting BMSC differentiation via the PI3K/AKT/β-catenin pathway.
Zhang P, Zheng H, Lin Z … +11 more , Zhang M, Yang L, Deng Z, Song C, Dai H, Su Y, Zhang R, Yu G, Luo J, Xu J, Luo F
Stem Cell Res Ther · 2026 Mar · PMID 41814363 · Full text
BACKGROUND: The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is a central pathological feature of osteoporosis (OP). The translocator protein (TSPO) is a multi...
BACKGROUND: The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is a central pathological feature of osteoporosis (OP). The translocator protein (TSPO) is a multifunctional protein, yet its precise role in bone metabolism remains elusive. This study aimed to investigate the role and mechanism of TSPO in OP pathogenesis. METHODS: We integrated bioinformatic analyses of human and mouse OP-related datasets and validated TSPO expression in BMSCs from osteoporotic patients and mouse models. Gain- and loss-of-function experiments in human BMSCs (h-BMSCs) assessed the impact of TSPO on proliferation, senescence, migration, and lineage differentiation. RNA sequencing and mechanistic rescue experiments were employed to identify the involved signaling pathway. The therapeutic effect of Adeno-associated virus 9 (AAV-9)-mediated TSPO silencing was evaluated in ovariectomized (OVX) mice. RESULTS: TSPO was significantly upregulated in BMSCs from both OP patients and preclinical models. Functionally, TSPO overexpression suppressed h-BMSC proliferation, migration, and osteogenesis while promoting senescence and adipogenesis. Conversely, TSPO knockdown enhanced cellular fitness and osteogenic capacity. Mechanistically, TSPO functioned as a critical upstream regulator of the PI3K/AKT/GSK-3β signaling axis, suppressing the downstream phosphorylation cascade and ultimately inhibiting β-catenin-mediated osteogenic transcription. Crucially, local TSPO silencing in OVX mice effectively improved bone microarchitecture, enhanced bone formation, and reduced marrow adiposity, concomitant with the reactivation of the PI3K/AKT/GSK-3β/β-catenin pathway. CONCLUSION: Our study identifies TSPO as a key pathogenic regulator that impairs osteogenesis by disrupting the PI3K/AKT/β-catenin pathway. Targeting TSPO presents a novel anabolic strategy for osteoporosis, potentially addressing the unmet clinical need for therapies that restore bone formation.
Engineering MSC-exosomes for diabetic bone regeneration: from mechanism to delivery.
Ran G, Jin H, Yang Q … +9 more , Zhai W, Lu J, Jiang W, Luo J, Fang S, Zhang Y, Liu H, Zuo J, Lin J
Stem Cell Res Ther · 2026 Mar · PMID 41808198 · Full text
The rapidly growing diabetic population is at high risk of dental implant failure due to a disrupted peri-implant immune microenvironment. Mesenchymal stem cells-derived exosomes (MSC-Exos) have emerged as a potent nanot...
The rapidly growing diabetic population is at high risk of dental implant failure due to a disrupted peri-implant immune microenvironment. Mesenchymal stem cells-derived exosomes (MSC-Exos) have emerged as a potent nanotherapeutic platform to remodel this hostile niche. Their mechanisms involve reprogramming macrophage polarization to alleviate inflammation, delivering pro-angiogenic miRNAs to restore vascular-osteogenic coupling, and modulating neuro-immune crosstalk to reestablish homeostasis. Collectively, these actions break the vicious cycle of impaired healing. Furthermore, engineering strategies such as membrane modification, integration with biomaterials, and preconditioning of parent cells can enhance the targeting, stability, and controlled release of MSC-Exos, thereby improving osseointegration outcomes in diabetic models. These engineering innovations, which focus on precise delivery and controlled release, are as critical to therapeutic development as elucidating the underlying biological mechanisms. This review systematically delineates the mechanisms by which MSC-Exos recalibrate the diabetic bone immune niche to foster osseointegration and critically discusses the clinical translation prospects of engineered exosome-based therapies.
Pretreated mesenchymal stromal cells and their secretome for kidney disease: mechanisms and applications.
Liu Q, Liu G, Sun D … +1 more , Li S
Stem Cell Res Ther · 2026 Mar · PMID 41803993 · Full text
The issue of kidney disease represents a significant global health challenge. While current treatment options may provide symptomatic relief, they are limited by several factors. Consequently, there is a pressing need to...
The issue of kidney disease represents a significant global health challenge. While current treatment options may provide symptomatic relief, they are limited by several factors. Consequently, there is a pressing need to create more effective therapeutic strategies. Mesenchymal stromal cell (MSCs) and their secretome have attracted considerable attention in the field of regenerative medicine owing to their multidirectional differentiation potential, immunomodulatory properties, and paracrine effects, which offer a promising solution to this challenge. However, direct transplantation of MSCs and their secretome faces problems such as low survival rate and unstable therapeutic effect in practical applications. These challenges have prompted researchers to explore strategies to enhance the therapeutic potential of MSCs and their secretory factors through pretreatment. This review summarizes the current research progress on pretreated MSCs and their secretome in the treatment of kidney diseases and discusses how various pretreatment approaches can enhance their therapeutic efficacy and clinical application in renal disorders, thereby providing insights for the future optimization and therapeutic use of MSCs.
SLIT3/ROBO1 axis contributes to angiogenic-osteogenic coupling in endothelial progenitor cells and peripheral blood mesenchymal stem cells.
Rong Q, Ma L, Wang M … +4 more , Liu Q, Zhang Y, Yuan Z, Tan X
Stem Cell Res Ther · 2026 Mar · PMID 41796379 · Full text
BACKGROUND: Early vascularization is one of the limitations of periodontal tissue engineering (PTE) based on mesenchymal stem cells (MSCs). Directed differentiation of endothelial progenitor cells (EPCs) into endothelial...
BACKGROUND: Early vascularization is one of the limitations of periodontal tissue engineering (PTE) based on mesenchymal stem cells (MSCs). Directed differentiation of endothelial progenitor cells (EPCs) into endothelial cells facilitates the osteogenic effect of MSCs. Therefore, this study constructed EPCs/peripheral blood derived-MSCs (EPCs/PBMSCs) sheets and evaluated their repair value and potential molecular mechanisms in bone regeneration. METHODS: Different ratios of EPCs and PBMSCs were co-cultured to prepare EPCs/PBMSCs sheets and the osteogenic differentiation was assessed. Exploring the bone regeneration properties of EPCs/PBMSC sheets in an animal model of alveolar bone defects. The effect of the SLIT3/ROBO1 axis on angiogenic-osteogenic coupling of EPCs/PBMSCs sheets was explored using exogenous modulation by shRNA lentivirus and neutralizing antibody. RESULTS: EPCs/PBMSCs sheets could form angiogenic-osteogenic coupling, and different ratios of EPCs/PBMSCs sheets had higher angiogenic and osteogenic differentiation properties than EPCs or PBMSCs alone, especially the ratio 4:6. Moreover, EPCs/PBMSCs sheets accelerated bone regeneration in the alveolar bone defect model and the treatment was superior to PBMSCs alone. The expression patterns of SLIT3 and ROBO1 were consistent with the angiogenic-osteogenic coupling of EPCs/PBMSCs sheets. Knockdown of SLIT3 in PBMSCs and/or neutralization of ROBO1 protein in EPCs effectively suppressed calcified nodule formation and markers expression of osteogenic differentiation and angiogenesis (ALP, RUNX2, OCN, Osx, EMCN, and CD31) in EPCs/PBMSCs sheets, and hindered its therapeutic effect in the alveolar bone defect model. CONCLUSION: EPCs/PBMSCs sheets ameliorate the limitations of early vascularization in PTE and the SLIT3/ROBO1 axis mediates the angiogenic-osteogenic coupling of EPCs/PBMSCs sheets, thereby augmenting their osteogenic effects.
WDR63 enhances the chondrogenic differentiation and regenerative potential of stem cell from apical papilla by facilitating vimentin function to promote mitochondrial fission.
Zhou J, Cao Y, Sun Z … +3 more , Huang Y, Zhu M, Fan Z
Stem Cell Res Ther · 2026 Mar · PMID 41796360 · Full text
BACKGROUND: Research on cartilage repair in the knee joint is crucial for treating knee arthritis or injuries. The application of mesenchymal stem cells (MSCs) for cartilage tissue regeneration represents a promising the...
BACKGROUND: Research on cartilage repair in the knee joint is crucial for treating knee arthritis or injuries. The application of mesenchymal stem cells (MSCs) for cartilage tissue regeneration represents a promising therapeutic approach. Among the critical aspects in cartilage formation, the enhancement of MSC chondrogenic differentiation stands as a pivotal challenge. WDR63 is a cytoplasmic dynein that plays a significant role in promoting stem cell differentiation and is closely associated with the cytoskeleton and energy metabolism processes. In the current study, our objective is to elucidate the phenotypic manifestations and mechanisms of WDR63 in relation to its chondrogenic differentiation function in MSCs. METHODS: Stem cells from apical papilla (SCAP) were used. The Alcian Blue staining technique, pellet culture system, and cell transplantation in rabbit knee cartilage defects were employed to assess the chondrogenic differentiation capabilities of MSCs. Western blot and real-time RT-PCR were utilized to investigate the molecular mechanisms involved. RESULTS: In vitro, WDR63 overexpression in SCAPs enhanced chondrogenic differentiation, as evidenced by upregulating collagen type II (COL2), collagen type V (COL5), and sex-determining region Y box protein 9 (SOX9), and robust pellet formation, whereas WDR63 knockdown produced opposite effects. In vivo, implantation of WDR63-overexpressing SCAP promoted cartilage repair in a rabbit osteochondral defect model, showing improved hyaline cartilage matrix deposition, higher COL2 expression, reduced collagen type X(COLX) expression, and increased collagen type Ι (COL1) expression in the subchondral bone. Mechanistically, WDR63 interacted and co-localized with vimentin (VIM), and its overexpression enhanced VIM expression and WDR63-VIM binding. WDR63 upregulates DRP1 expression, and rescues the Mdi-suppressed mitochondrial fission. CONCLUSIONS: WDR63 may promote chondrogenic differentiation of SCAPs by interacting with VIM and enhancing its expression, potentially through facilitating mitochondrial fission.
Dental pulp stem cells maintain epigenetic chromatin architecture remodeling primed by the etiological stimulus of biliary atresia.
Sonoda S, Yu L, Dai L … +15 more , Kyumoto-Nakamura Y, Yoshimaru K, Yuniartha R, Liu Y, Sharifa MM, Murata S, Zakaria MF, Kato H, Uehara N, Fukumoto S, Yamaza H, Matsuura T, Taguchi T, Tajiri T, Yamaza T
Stem Cell Res Ther · 2026 Mar · PMID 41794760 · Full text
BACKGROUND: Biliary atresia (BA) is a nongenetic cholangiopathy characterized by biliary obliteration. However, the underlying pathological mechanism remains unclear. We aimed to explore the epigenetic BA pathology by us...
BACKGROUND: Biliary atresia (BA) is a nongenetic cholangiopathy characterized by biliary obliteration. However, the underlying pathological mechanism remains unclear. We aimed to explore the epigenetic BA pathology by using BA-specific deciduous dental pulp stem cells (BA-SHED), which develop in parallel with cholangiocyte progenitor cells in human embryos. METHODS: BA-SHED were isolated from human exfoliated deciduous teeth of patients with BA using the colony-forming unit fibroblast method. After sequential stimulation with cytokines and chemicals in cultured BA-SHED, the in vitro bile duct-forming capacity was analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunofluorescence. Expression of hepatocyte nuclear factor 6 (HNF6) and transforming growth factor beta receptor 2 (TGFBR2) was analyzed using immunoblotting and RT-qPCR. The regulation of chromatin architecture at the HNF6 promoter was analyzed using nuclease-accessible chromatin-qPCR and chromatin immunoprecipitation-qPCR. RESULTS: BA-SHED showed an inheritable increase in HNF6 levels, resulting in TGFBR2 suppression and deficiency in bile duct formation. BA-SHED also accumulated Brahma and P65 complexes around the HNF6 promoter with chromatin architecture remodeling. Tumor necrosis factor-alpha and interferon-gamma co-stimulation mimicked the epigenetic signatures of BA-SHED. CONCLUSION: The present epigenetic memory in BA-SHED implies that BA-SHED imprint bile duct deficiency through TGFBR2 dysregulated by the HNF6 promoter activation epigenetically. Thus, BA-SHED are a potential model for expanding our knowledge in BA research.
Schisantherin A promotes neural differentiation of stem cells from apical papilla to improve mandibular development via mental nerve repair.
Du L, Li A, Tang Z … +6 more , Yang H, Shi X, Wang S, Qiu Z, Yang X, Huang Y
Stem Cell Res Ther · 2026 Mar · PMID 41792814 · Full text
BACKGROUND: Evidence shows neural involvement in bone remodeling; regulating maxillofacial nerve repair modulates jawbone. Neural stem cell (NSC) therapy is limited by sources/ethics, but neural crest-derived dental mese...
BACKGROUND: Evidence shows neural involvement in bone remodeling; regulating maxillofacial nerve repair modulates jawbone. Neural stem cell (NSC) therapy is limited by sources/ethics, but neural crest-derived dental mesenchymal stem cells (MSCs) like stem cells from the apical papilla (SCAPs) have strong neuroregenerative potential for NSC transdifferentiation. Schisantherin A (Sch-A), neuroprotective, enhances NSC proliferation/differentiation. This study explores optimal Sch-A concentration/duration for SCAP neural differentiation and effects on rat mental nerve repair/mandibular development. METHODS: SCAPs' mesenchymal stem cell properties were verified via flow cytometry and trilineage differentiation. Effects of different Sch-A concentrations were evaluated using CCK-8, colony formation, scratch assay, qRT-PCR, immunofluorescence, and Western blot. Transcriptome sequencing identified underlying mechanisms and determined optimal. A mental nerve injury model was established in 4-week-old SD rats (five groups; n = 4 per group) to assess neurorepair, functional recovery, and mandibular development following transplantation of Sch-A-induced SCAPs. RESULTS: Treatment with 10 mol/L Sch-A for 1 week induced robust neural differentiation in SCAPs, with high expression of nestin and NSE. Mental nerve-injured SD rats exhibited reduced lip sensation, abnormal nerve morphology, and inhibited transverse development of the anterior mandibular. Transcriptome analysis revealed Sch-A primarily acts via neuroactive ligand-receptor interaction pathway. Transplantation of induced SCAPs promoted nerve repair and restored mandibular development. CONCLUSION: Sch-A at 10 mol/L concentration promotes the transdifferentiation of SCAPs into neural stem cell-like cells primarily through the neuroactive ligand-receptor interaction pathway. These Sch-A induced SCAPs effectively repair mental nerve injury and facilitate normal mandibular development.
BMSC exosomes promote neurogenesis and alleviate behavioral deficits in chronic traumatic encephalopathy: an animal model-based study.
Liu P, Bai Z, Yang Y … +3 more , Li X, Xia J, Yang Q
Stem Cell Res Ther · 2026 Mar · PMID 41787581 · Full text
Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder, poses a significant threat to human health. The lack of validated animal models has impeded mechanistic studies and the development of tre...
Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder, poses a significant threat to human health. The lack of validated animal models has impeded mechanistic studies and the development of treatments for CTE. Recent evidence suggests that bone marrow mesenchymal stem cell-derived exosomes (BMSC-exos) represent a promising strategy for treating central nervous system injuries; however, their efficacy and mechanisms of action in CTE remain unexplored. In this study, we developed and optimized a CTE mouse model that recapitulates the core clinical features observed in CTE patients, including the delayed symptom onset. Using this model, we investigated the therapeutic effects of BMSC-exos. Our results indicate that BMSC-exos ameliorated anxiety-like behaviors and cognitive deficits in CTE mice, restoring them to levels comparable to those in noninjured control mice. Mechanistically, analysis of the hippocampal subgranular zone (SGZ) revealed that BMSC-exos restored the chronic CTE-induced reduction in the number of doublecortin (DCX)-positive immature neurons without altering the population of Sox2-Nestin-double-positive neural stem cells, indicating a primary effect on promoting neuronal differentiation efficiency or immature neuron survival rather than stem cell proliferation. Furthermore, BMSC-exos preserved neuronal structural integrity during late-stage CTE, indicating a critical role in maintaining synaptic plasticity and dendritic complexity. Collectively, our study provides promising evidence for the therapeutic potential of BMSC-exos in CTE, offering new insights for future CTE therapeutics.
The efficacy and safety of MSCs in GVHD prevention and the treatment of SR-aGVHD: a systematic review and meta-analysis of randomized controlled trials.
Wu S, Lu W, Xie A … +8 more , Wang J, Zeng W, Chen C, Wu N, Ye J, Zou Z, Li L, Zhou L
Stem Cell Res Ther · 2026 Mar · PMID 41787572 · Full text
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a cornerstone in the treatment of hematological disorders. However, its application is frequently complicated by acute and chronic graft-versus-host disease (...
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a cornerstone in the treatment of hematological disorders. However, its application is frequently complicated by acute and chronic graft-versus-host disease (aGVHD/cGVHD), pathological conditions in which donor-derived immune cells attack host tissues. With suboptimal survival rates and limited therapeutic options, GVHD remains a major clinical challenge. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality due to their immunomodulatory capabilities, yet standardized protocols for their use in preventing or treating GVHD have not been established. METHODS: We performed a comprehensive literature search of PubMed, Web of Science, EMBASE, and the Cochrane Library up to 10 February 2025 to identify eligible randomized controlled trials (RCTs). Study selection was based on the PICOS framework, and the risk of bias was assessed using appropriate quality appraisal tools. Outcome data were systematically extracted and synthesized via meta-analysis. RESULTS: A total of 15 RCTs were included. The meta-analysis revealed that MSC administration significantly reduced the incidence of aGVHD (OR: 0.47; 95% CI 0.32-0.71; p = 0.00003) and cGVHD (OR: 0.50; 95% CI 0.34-0.74; p = 0.0005) compared with controls. MSC therapy was also associated with improved response rates in steroid-refractory aGVHD (SR-aGVHD) (OR: 1.50; 95% CI 1.04-2.17; p = 0.03). CONCLUSION: MSCs demonstrate efficacy in preventing both aGVHD and cGVHD following HSCT, particularly in moderate to severe forms. A dose range of 1 × 10⁶ to < 4 × 10⁶ cells/kg was associated with optimal prophylactic outcomes. For SR-aGVHD, MSC infusion resulted in significantly higher remission rates compared to conventional treatments, especially in severe cases.
Retinoblastoma: unveiling molecular pathogenesis and pioneering organoid-driven therapeutic innovations.
Li H, Jin C
Stem Cell Res Ther · 2026 Mar · PMID 41782059 · Full text
Retinoblastoma (RB), which is the most common pediatric intraocular malignancy driven by RB1 inactivation, presents with clinical challenges, such as treatment toxicity, relapse, and resistance. Traditional models inadeq...
Retinoblastoma (RB), which is the most common pediatric intraocular malignancy driven by RB1 inactivation, presents with clinical challenges, such as treatment toxicity, relapse, and resistance. Traditional models inadequately replicate human RB genetics or tumor heterogeneity, warranting the development of advanced in vitro platforms. Retinal organoids generated from human pluripotent or patient-specific stem cells enable three-dimensional(3D) modeling of the tumor microenvironment, drug screening, and mechanistic studies. This review summarizes RB pathogenesis, including RB1 loss, MYCN amplification, epigenetic dysregulation (e.g., METTL3-mediated m6A), and dysregulated pathways (PI3K/AKT/mTOR, Hedgehog), and highlights CRISPR-engineered organoids for identifying cone precursors as tumor origins and validating therapies (CDK4/6 inhibitors and sunitinib). Despite these advances, organoid applications are limited by high costs, variable success rates, incomplete immune/vascular mimicry, and limited scalability. Current microfluidic systems partially address vascularization but lack functional perfusion. Future efforts should integrate multiomics, refine vascularization via 3D bioprinting, and develop immunocompetent models to address the disparity between preclinical research and clinical application. Organoid technology has the potential to advance personalized therapies and ultimately enhance the survival and quality of life of patients with RB worldwide.
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