Stem Cell Res Ther [JOURNAL]
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200 papers
The impact of T cell exhaustion in hematopoietic stem cell transplantation.
Li Y, Guo H, Zhang Y … +4 more , Chen J, Zhong L, Huang X, Li Y
Stem Cell Res Ther · 2026 Jun · PMID 42366382 · Full text
T cell exhaustion is a hallmark of failure to control cancer and chronic infection. In hematological malignancies, T cell exhaustion not only relates to disease progression but also impacts the outcome of hematopoietic s...
T cell exhaustion is a hallmark of failure to control cancer and chronic infection. In hematological malignancies, T cell exhaustion not only relates to disease progression but also impacts the outcome of hematopoietic stem cell transplantation (HSCT), which may be due to a low graft-versus-leukemia (GVL) effect and a low anti-virus infection capacity. However, a deeper mechanistic understanding of the impact of T cell exhaustion in HSCT remains to be characterized. In this review, we summarize the characteristics of T cell exhaustion, functional alterations in T cells post-transplantation, the role of T cell exhaustion in post-transplant complications, and related therapeutic strategies.
Cardiac organoids in toxicology: from construction strategies and research trends to precision screening applications.
Qiao L, Xu Y, Wang X … +6 more , Zhu Y, Zhang T, Niu Y, Chen M, Yang S, Liang G
Stem Cell Res Ther · 2026 Jun · PMID 42365336 · Full text
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with significant attention focused on the development of therapeutic drugs and research into pathogenic mechanisms. In the real world, cardiotoxici...
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, with significant attention focused on the development of therapeutic drugs and research into pathogenic mechanisms. In the real world, cardiotoxicity induced by multiple factors commonly exists and is closely associated with cardiovascular diseases. Traditional toxicity testing models (such as animal experiments and two-dimensional cell cultures) have limited clinical translation value due to species differences, inability to simulate the complex microenvironment of the human body, and cellular interactions. Cardiac organoids, as an emerging three-dimensional (3D) culture platform, possess 3D structure, multicellular composition, organ-specific functions, and self-organizing capabilities, which can highly mimic the physiological and pathological characteristics of the heart, providing a more precise humanized model for the study of cardiovascular disease mechanisms, drug development, and toxicity assessment. This paper systematically reviews the construction strategies of cardiac organoids and their application progress in toxicology: Firstly, it explores the construction standards and technical optimization of cardiac organoids, focusing on human-engineered heart tissue (hEHT) models and various cardiac organoid models that mimic the human heart, with particular attention to their unique characteristics, utility, and limitations. Secondly, through bibliometric analysis using CiteSpace, it reveals research hotspots and trends in cardiac organoid applications for toxicology, specifically by extracting collaboration networks, conducting co-citation analysis, and co-occurrence analysis. Finally, it summarizes specific applications of cardiac organoids in toxicology, including drug toxicity assessment, environmental pollutant toxicity evaluation, cardiac developmental toxicity studies, disease model construction, and multi-organ cascade studies for systemic toxicity assessment.
Identification of a long-term surviving human mesenchymal stromal cell subpopulation and implications for recessive dystrophic epidermolysis bullosa treatment.
Bonnet des Claustres M, Gaucher S, Carbone F … +6 more , Peltzer J, Luka M, Masson C, Nitschké P, Hovnanian A, Titeux M
Stem Cell Res Ther · 2026 Jun · PMID 42365332 · Full text
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by loss-of-function pathogenic variants in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from...
BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disease caused by loss-of-function pathogenic variants in COL7A1 encoding type VII collagen (C7). Patients with RDEB suffer since birth from skin and mucosal blistering and develop severe local and systemic complications resulting in poor prognosis. Mesenchymal stromal cells (MSCs) have demonstrated their potential to enhance wound healing and reduce skin inflammation in RDEB patients due to their anti-inflammatory properties and capacity to express C7. We aim to optimize in vitro conditioning of human bone marrow-derived MSCs (BM-MSCs) to improve their limited survival following local injection in a murine model. METHODS: BM-MSCs from healthy human donors were transduced with a lentiviral vector encoding firefly luciferase and mCherry reporter proteins and then subjected to various culture conditions: monolayer on plastic or spheroid culture, either in hypoxia (5% O) or in normoxia (21% O). These cells were subsequently injected intradermally (ID) in immunodeficient mice and their survival was assessed by in vivo imaging. BM-MSCs populations were analyzed prior to injection by single-cell RNA sequencing (scRNAseq). Murine skin injected with BM-MSCs were sampled two months post-injection and the surviving subpopulations were characterized by spatial transcriptomic. RESULTS: scRNAseq analysis revealed marked variations between monolayer and spheroid conditions, which were significantly impacted by oxygen level. Although most injected cells gradually died within the first 2 months in all tested conditions, 1% of live bioluminescent cells persisted for 54 up to 61 weeks post-injection. Spatial transcriptomics data analysis demonstrated that all surviving cells, regardless of their in vitro preconditioning, retained the expression of the MSC markers THY1, ENG, and NT5E, shared features with fibroblasts, and exhibited enriched expression in genes related to extracellular matrix and collagen fibril organization, which are key processes in wound healing. Spatial transcriptomic and scRNAseq data integration suggested that surviving BM-MSCs were initially present in the injected population, regardless of their culture condition. Remarkably, none of the in vitro preconditioning strategies appeared to affect their survival capacity or functional properties following local injection. CONCLUSIONS: The identification and characterization of a BM-MSC subpopulation capable of long-term survival following ID injection hold promise for the development of improved cell therapy protocols for RDEB.
Dexamethasone reduces osteogenic potential through suppressing retinoic acid signaling via NF-κB/CYP26B1 axis in mesenchymal stem cells.
Ye AH, Wang YM, Wan XY … +8 more , Liu J, Tang N, Liu WT, Cai J, He DM, He BC, He WG, Chen L
Stem Cell Res Ther · 2026 Jun · PMID 42363259 · Full text
OBJECTIVE: Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis, which characterized by the decreased bone strength and increased fracture risk. But the pathogenic causes of GIOP remains n...
OBJECTIVE: Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis, which characterized by the decreased bone strength and increased fracture risk. But the pathogenic causes of GIOP remains not completely yet. In this study, we investigated the effect of Cyp26b1, a key enzyme for all-trans retinoic acid (ATRA) degradation, on the osteogenic inhibitory effect of dexamethasone (DEX) in mesenchymal stem cells (MSCs) and revealed the possible mechanism through which DEX regulates the expression of Cyp26b1. METHODS: MSCs were induced with osteogenic induction medium in vitro to establish the osteogenic model, and high concentration (10 M) of DEX was utilized to treat MSCs to exert its osteogenic inhibitory effect. ATRA content was detected with ELISA, real-time polymerase chain reaction (RT-PCR), western blot, and immunofluorescence staining were employed to detect hall markers for osteogenic differentiation. Chromatin immunoprecipitation (ChIP) assay was used to detect the binding of promoter region of target gene. The rat GIOP model was constructed by intraperitoneal injection of DEX, and the adeno-associated virus was injected via tail vein after the model was constructed. The bone samples were subjected with µ-CT scanning, H&E, and Masson trichrome staining, respectively. RESULTS: DEX (10 M) decreased the levels of osteogenic markers induced by osteogenic induction medium (OIM) in MSCs, and it was almost reversed by ATRA. But this effect of ATRA was obviously eliminated by overexpression of Cyp26b1. The mRNA expression level of Cyp26b1 was significantly increased by DEX (10 M), and the content of retinoic acid was decreased in cells. Osteogenic markers decreased by DEX (10 M) were recovered by Cyp26b1 knockdown, whereas Cyp26b1 overexpression exerted the opposite effect. DEX (10 M) increased the activation of NF-κB signaling, and the osteogenic inhibitory effects of DEX were ameliorated by NF-κB inhibitors which was almost abolished by Cyp26b1 overexpression. The mRNA level of Cyp26b1 was up-regulated by DEX (10 M and 10 M), but the degradation of Cyp26b1 was promoted by DEX (10 M) only via the lysosomal pathway. CONCLUSION: The osteogenic inhibitory effect of high concentration of DEX may be resulted from the disturbance of retinoic acid signaling. The expression of Cyp26b1 can be up-regulated by either low or high concentration of DEX, but its degradation can only be inhibited by high concentration of DEX. The effect of DEX on Cyp26b1 expression was partially mediated by activating NF-κB signaling in MSCs.
Endothelial-immune cells-on-chip for multiplex evaluation of drug responses through patient plasma screening.
Lee KL, Wee HS, Teng ZY … +8 more , Tay HM, Chee YJ, Tan EXX, Dan YY, Muthiah MD, Dalan R, Hou HW, Cheung C
Stem Cell Res Ther · 2026 Jun · PMID 42351308 · Full text
Most organ-on-chip models focus on parenchymal cell function, overlooking the critical role of endothelial-immune interactions in metabolic disease pathophysiology. Drugs for metabolic conditions, such as SGLT2 inhibitor...
Most organ-on-chip models focus on parenchymal cell function, overlooking the critical role of endothelial-immune interactions in metabolic disease pathophysiology. Drugs for metabolic conditions, such as SGLT2 inhibitors, provide not only metabolic improvements but also vascular-protective effects, underscoring the need for human platforms that capture immunovascular dynamics. Here, we developed a human endothelial-immune cells-on-chip system integrating patient-derived blood outgrowth endothelial cells, T cells, and hepatocytes to model the liver sinusoidal microenvironment. Using plasma from type 2 diabetes patients treated with dapagliflozin, the platform revealed reduced endothelial inflammatory activation, attenuated T cell migration, and decreased hepatocyte lipid accumulation, indicating systemic modulation of vascular and hepatic phenotypes. Despite the presence of endothelial SGLT2 protein expression, glucose uptake in vitro was unaltered by dapagliflozin, suggesting these beneficial effects might occur indirectly via plasma factors. Our multiplexed, human-relevant cellular platform enables simultaneous assessment of endothelial, immune, and hepatic responses, offering a versatile tool for personalized plasma-based drug screening and preclinical evaluation of vascular-protective therapies in metabolic diseases.
A 3D-printed extravascular stent containing sirtuin-3 engineered human bone marrow mesenchymal stem cells maintains venous graft patency.
Liu K, Sun X, Jiao X … +12 more , Chao L, Zhang B, Liu C, Wu J, Huang M, Cai P, Li X, Zhao Y, Tian X, Li RK, Chen W, Tian H
Stem Cell Res Ther · 2026 Jun · PMID 42351307 · Full text
BACKGROUND: Coronary artery bypass grafting (CABG) reconstructs the blood supply for treating coronary heart disease. One of the most used conduits is the great saphenous vein, but its effect is limited, owing to lower l...
BACKGROUND: Coronary artery bypass grafting (CABG) reconstructs the blood supply for treating coronary heart disease. One of the most used conduits is the great saphenous vein, but its effect is limited, owing to lower long-term patency versus arterial grafts. This study devised a 3D bio-printed stent, comprising of genetically modified human bone marrow mesenchymal stem cells (BMSCs), to improve venous graft patency. METHODS: BMSCs and endothelial cells (ECs) were obtained from sternal bone marrow and discarded saphenous veins, respectively. BMSCs were transduced with lentivirus overexpressing sirtuin-3 (SIRT3) and seeded on a 3D bio-printed matrix stent, comprising of hyaluronic acid methacryloyl and gelatin methacryloyl (HAMA/GelMA). A rat CABG model was established, via generating a jugular vein-common carotid artery arteriovenous graft. The SIRT3-BMSC-seeded stent was "wrapped" around this venous graft, serving as an extravascular stent. An in vitro model was also devised, in which lipopolysaccharide (LPS)-pre-treated ECs were co-cultured with SIRT3-BMSCs, followed by evaluating mitochondrial transferal and tunneling nanotube (TNT) formation-related functional changes. Immunoprecipitation was used to examine SIRT3-vasodilator-simulated phosphoprotein (VASP) interactions. RESULTS: Rat arteriovenous graft model found that SIRT3-BMSC+stent, compared to Control, Stent, and BMSC+stent groups, had the greatest graft vessel diameter, maximum blood flow velocity during systole and CD31 EC area, along with the lowest cell proliferation and inflammatory cell infiltration; therefore, SIRT3-BMSC+stent had the greatest inhibitory effects on venous graft neointimal formation. In vitro, LPS-pre-treated ECs, after co-culture with SIRT3-BMSCs, restored endothelial, along with lowering mesenchymal marker expression. Furthermore, mechanistic analyses revealed increased SIRT-BMSC-to-LPS-pre-treated EC mitochondrial transfer, facilitated by TNTs formed between SIRT3-BMSCs and ECs. This mitochondrial transfer was mediated via SIRT3-VASP interactions, in which SIRT3 deacetylates VASP to promote TNT. CONCLUSION: SIRT3-BMSC/HAMA/GelMA extravascular stent could effectively lower arteriovenous graft dilation and inhibit neointimal formation, possibly via SIRT3 deacetylation of VASP, thereby promoting TNT formation, and subsequently, mitochondrial transfer from BMSCs to ECs to improve EC function. Thus, the extravascular stent was able to provide external support, along with facilitating BMSC therapeutic effects.
Pathological mechanisms and therapeutic potential of MSC-Exos in ischemic stroke management.
Wei X, Zhang Z, Han W … +6 more , Du W, Li Z, Deng J, Yang Q, Peng T, Zhu D
Stem Cell Res Ther · 2026 Jun · PMID 42351306 · Full text
Cerebral ischemia-reperfusion injury (CIRI) represents a critical pathological challenge in the management of ischemic stroke, substantially limiting the clinical efficacy and success rates of neurosurgical interventions...
Cerebral ischemia-reperfusion injury (CIRI) represents a critical pathological challenge in the management of ischemic stroke, substantially limiting the clinical efficacy and success rates of neurosurgical interventions, brain tissue therapies, and cell transplantation strategies. The complex pathological mechanisms underlying CIRI, which include inflammatory responses, oxidative stress, ferroptosis, apoptosis, and blood-brain barrier disruption, significantly hinder neurological recovery. Mesenchymal stem cells-derived exosomes (MSC-Exos) have emerged as a promising acellular therapeutic strategy owing to their low immunogenicity, ability to cross the blood-brain barrier, and multi-target regulatory properties. This review compares MSC-Exos derived from multiple sources and summarises their mechanisms of action and therapeutic potential in CIRI. Despite ongoing challenges in standardisation and safety evaluation, accumulating preclinical evidence highlights their potential for future clinical translation and precision regenerative medicine.
Endothelial progenitor cell susceptibility to DNA damaging and DDR-modulating compounds determines endothelial differentiation accuracy.
Federmann S, Westerhoff M, Reichert AS … +1 more , Fritz G
Stem Cell Res Ther · 2026 Jun · PMID 42351287 · Full text
The clinical use of the anticancer drug doxorubicin (Dox) is limited by irreversible cardiotoxicity. The pathophysiological relevance of different cardiac cell types, including endothelial progenitor cells (EPC), in this...
The clinical use of the anticancer drug doxorubicin (Dox) is limited by irreversible cardiotoxicity. The pathophysiological relevance of different cardiac cell types, including endothelial progenitor cells (EPC), in this process is unclear. Since progenitor cells are particularly relevant for tissue regeneration, we hypothesize that residual damage resulting from Dox-based therapeutic regimen may influence their endothelial differentiation accuracy. Therefore, we comparatively investigated the response of murine embryonic stem cells (mESC), endothelial progenitor cells (EC d4) and terminally differentiated endothelial-like cells (EC d6) following exposure to Dox and selected pharmacological inhibitors of DNA repair/DNA damage response (DDR) (RAD51i B02; HDACi entinostat (EST)). We show that EC d4 exhibit enhanced Dox sensitivity as compared to mESC and EC d6. EdU incorporation and replication fork progression analyses revealed pronounced agent-specific differences between mESC, EC d4 and EC d6. Furthermore, DNA damage formation varied in a drug-dependent manner, with mESC showing enhanced residual levels of DNA single-strand breaks (SSB) as compared to EC d4 and EC d6 while EC d6 revealed highest levels of DNA double-strand breaks (DSB). Dox treatment of EC d4 did not prevent their further differentiation into EC d6. However, it caused several functional impairments in the surviving EC d6 progeny, including defects in mitochondrial homeostasis, endothelial barrier function related to cell-cell adhesion factors (ZO1, VE-cadherin), cytokine response and low-density lipoprotein (LDL) uptake. This is accompanied by increased senescence. Summarizing, we demonstrate both overlapping and agent-specific responses of mESC, EC d4 and EC d6 to Dox and DNA repair/DDR inhibitors. Notably, drug treatment of EPC (EC d4) causes multiple dysfunctions in differentiated EC d6. Hence, pharmacological measures aiming to specifically protect EPC from Dox-induced damage are suggested to foster the maintenance of healthy endothelial functionality during regeneration, thereby lowering the risk of detrimental late cardiotoxicity resulting from Dox-based anticancer regimen.
3D printed nano-hydroxyapatite scaffold combined with BMSCs cell sheet containing concentrated growth factor (CGF) for enhancing bone regeneration.
Shao Q, Shi J, Lu J … +1 more , Tian Y
Stem Cell Res Ther · 2026 Jun · PMID 42351242 · Full text
BACKGROUND: Craniofacial bone defects represent significant clinical challenges resulting from diverse etiological factors. Despite advancements in biomaterials science, autologous tissue transplantation remains the gold...
BACKGROUND: Craniofacial bone defects represent significant clinical challenges resulting from diverse etiological factors. Despite advancements in biomaterials science, autologous tissue transplantation remains the gold standard for craniofacial reconstruction due to the limitations of existing materials in replicating the complexity and functionality of native tissues. OBJECTIVE: This study aimed to investigate the efficacy of combining 3D-printed nano-hydroxyapatite (n-HA) scaffolds with concentrated growth factor-enriched cell sheets (CGF-BMSCs-CS) for bone defect repair, exploring their synergistic effects on osteogenesis and tissue regeneration. METHODS: Bone marrow mesenchymal stem cells (BMSCs) were utilized to fabricate CGF-enriched cell sheets. 3D-printed porous n-HA scaffolds (5 mm diameter, 1 mm thickness) were prepared and wrapped with CGF-BMSCs-CS to form composite scaffolds. Four experimental groups were established: control, n-HA alone, CGF-BMSCs-CS alone, and the composite n-HA/CGF-BMSCs-CS. Osteogenic potential was evaluated through alkaline phosphatase (ALP) activity assays and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis of osteogenesis-related gene expression. Sprague-Dawley rats were randomly assigned to these groups for a cranial defect model. Micro-computed tomography (µCT) was performed at 6 and 12 weeks post-surgery to assess bone regeneration metrics, including bone volume fraction (BV/TV), trabecular number (Tb.N), and trabecular thickness (Tb.Th). RESULTS: Scanning electron microscopy (SEM) confirmed the n-HA scaffold's uniform porosity and structural integrity. The CGF-BMSCs-CS exhibited optimal thickness and viscosity for tissue engineering applications. The composite group demonstrated significantly elevated ALP activity and upregulated expression of osteogenesis-related genes, indicating enhanced osteogenic capacity. µCT analysis revealed superior bone formation and osseointegration in the composite scaffold group compared to other groups. This was further supported by significantly higher bone mineral density (BMD) values at both time points (p < 0.05). Histological evaluation via hematoxylin and eosin (H&E) staining showed increased osteocyte activity, neovascularization, and trabecular bone formation in the composite group. CONCLUSIONS: We innovatively integrated 3D printed n-HA scaffolds with CGF BMSCs CS, which combines mechanical stability with enhanced osteogenic potential for craniofacial bone defect repair, promoting bone healing. This innovative strategy provides promising prospects for advancing bone tissue engineering and regenerative medicine.
Exosomal miR-181d-5p derived from distal airway stem cells inhibit apoptosis of pulmonary vascular endothelial cells in COPD mice by targeting PDAP1.
Song Q, Liu C, Lin L … +5 more , Zhou A, Li T, Zhang P, Zeng Y, Chen P
Stem Cell Res Ther · 2026 Jun · PMID 42351225 · Full text
BACKGROUND: This study was to investigate the role of exosomes derived from distal airway stem cells (DASC) in apoptosis of pulmonary vascular endothelial cells (PVEC) in chronic obstructive pulmonary disease (COPD) and...
BACKGROUND: This study was to investigate the role of exosomes derived from distal airway stem cells (DASC) in apoptosis of pulmonary vascular endothelial cells (PVEC) in chronic obstructive pulmonary disease (COPD) and to explore the potential mechanisms. METHODS: Cigarette smoke extract (CSE) plus cigarette smoke (CS)-induced COPD mice were treated with DASC and exosomes. The microRNA (miR) sequencing of exosomes was performed to explore the underlying mechanisms. We determined the expression of miR-181d-5p and PDAP1 in patients with COPD. RESULTS: Compared with control mice, DASC and exosomes derived from DASC could alleviate emphysema changes, decrease the mean linear intercept and alveolar destructive index, reduce apoptosis of PVEC in COPD mice. Furthermore, miR-181d-5p was significantly decreased in exosomes derived from COPD mice DASC when compared with exosomes derived from normal mice DASC. The knockdown of miR-181d-5p in exosomes derived from DASC could weaken its effects in alleviating emphysema and apoptosis of PVEC, increase the expression of PDAP1, and decrease the expression of miR-181d-5p. The overexpression of miR-181d-5p and knockdown of PDAP1 could significantly reduce apoptosis in CSE-induced PVEC. Furthermore, the overexpression of PDAP1 could reverse the anti-apoptotic effect of miR-181d-5p on CSE-induced PVEC. Finally, the expression of miR-181d-5p was decreased in patients with COPD and positively related to pulmonary function, while the expression of PDAP1 was increased and negatively related to pulmonary function. CONCLUSIONS: Exosomes derived from DASC could alleviate lung injury in COPD. The mechanism may be to reduce the apoptosis of PVEC by delivering miR-181d-5p by targeting PDAP1.
Mesenchymal stem cell-derived microvesicles confer protection against rheumatoid arthritis-associated interstitial lung disease.
Liang X, Li Y, Tang Z … +8 more , Zhang Q, Tan C, Wu T, Huang D, Wu Y, Cheng L, Luo Y, Liu Y
Stem Cell Res Ther · 2026 Jun · PMID 42351197 · Full text
BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious condition with few treatment options and a poor outlook. Mesenchymal stem cell-derived microvesicles (MSC-MVs) offer a potential...
BACKGROUND: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious condition with few treatment options and a poor outlook. Mesenchymal stem cell-derived microvesicles (MSC-MVs) offer a potential cell-free therapy, but their effectiveness and the role of their miRNA content in RA-ILD are not well understood. METHODS: A mouse model of comorbid RA-ILD was created using collagen-induced arthritis and bleomycin-induced pulmonary fibrosis. Mice received high- or low-dose MSC-MVs via tail vein injection. The treatment effectiveness was evaluated by assessing arthritis severity and pulmonary fibrosis through clinical scores, imaging, histopathology, lung function, and lung coefficients. The expression of fibrotic markers in the lungs was measured using immunohistochemistry and Western blotting. Small RNA sequencing of MSCs-MVs was conducted to explore the underlying mechanism. RESULTS: Administering MSCs-MVs significantly reduced the severity of arthritis and pulmonary fibrosis. Treated mice had better joint and lung scores, with decreased fibrotic areas and lower levels of fibrotic proteins such as anti-α-smooth muscle actin, collagen I, and fibronectin. Small RNA sequencing revealed that MSC-MVs contain microRNAs (miRNAs) (e.g., miR-148a-3p) that target critical pathways in RA-ILD, such as transforming growth factor-β (TGF-β) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling. CONCLUSIONS: Our research revealed that MSCs-MVs significantly protect against RA-ILD in a comorbid model. This protective effect is likely facilitated by the transfer of specific miRNAs that modulate essential profibrotic and inflammatory pathways. These results underscore the therapeutic potential of MSC-MVs as an innovative cell-free approach for RA-ILD treatment and identify miRNA-mediated pathway regulation as a pivotal mechanism.
Recent advances on anti-scarring properties of amniotic membrane: emerging strategies and clinical potentials in regenerative medicine.
Soltani K, Niknejad F, Sadrinasab S … +4 more , Gholinezhad Y, Mazloomnejad R, Tayebi T, Niknejad H
Stem Cell Res Ther · 2026 Jun · PMID 42343448 · Full text
Scarring remains an inevitable consequence of adult wound healing, often accompanied by functional, aesthetic, and psychological burdens. In contrast, fetal wound healing follows a fundamentally different trajectory, cha...
Scarring remains an inevitable consequence of adult wound healing, often accompanied by functional, aesthetic, and psychological burdens. In contrast, fetal wound healing follows a fundamentally different trajectory, characterized by minimal inflammation, abundant hyaluronic acid, elevated type III collagen, and balanced matrix remodeling, culminating in regeneration without scar formation. This regenerative capacity is largely absent in adult tissues, which is the main incentive for understanding the pathophysiology of scarless healing phenotype to replicate such outcomes in adult tissues. The human amniotic membrane (hAM), as an embryogenic derivative, shares many structural and biochemical properties with fetal cutaneous tissue, positioning it as a promising biological tool to bridge adult wound healing toward a scarless, fetal-like outcome. hAM contains a rich milieu of growth factors, anti-inflammatory cytokines, and extracellular matrix components that support epithelialization, angiogenesis regulation, fibroblast modulation, and myofibroblast suppression. These effects are mediated through modulation of key signaling pathways including TGF-β/SMAD, PI3K/AKT, Wnt/β-catenin, and MAPK cascades; each central to the orchestration of fibrosis and regeneration. Furthermore, hAM's angio-modulatory behavior, antioxidant capacity, and context-dependent immune regulation contribute to a healing microenvironment that more closely mimics fetal conditions. In this review, we highlight the unique biology of fetal scarless healing which can be harnessed through the use of amniotic membrane-based therapies in adults. We highlight how the properties of hAM can help shift adult wound healing toward a more regenerative, less fibrotic outcome. We also examine different ways hAM is processed and applied in clinical settings and processing effects on anti-scar characteristic of hAM and discuss the main challenges that still need to be addressed, such as product standardization and optimizing treatment protocols, in a biomimetic way from scarless wound healing in embryo. Altogether, application of hAM presents a compelling and biologically sound approach to promote scarless wound healing in adult patients, a longstanding goal in regenerative medicine.
Mapping the evolutionary landscape of intestinal organoids: from self-organization biology to precision medicine.
Liang F, Pei Z, Wang X … +1 more , Zhang K
Stem Cell Res Ther · 2026 Jun · PMID 42343431 · Full text
The advent of intestinal organoids has fundamentally transformed biomedical research by providing a physiological ex vivo model that recapitulates native tissue architecture. Despite an exponential surge in publications,...
The advent of intestinal organoids has fundamentally transformed biomedical research by providing a physiological ex vivo model that recapitulates native tissue architecture. Despite an exponential surge in publications, a comprehensive mapping of the field's evolutionary trajectory remains lacking. This study employs bibliometric analysis to dissect the global landscape of intestinal organoid research from 1986 to 2025, utilizing data from the Web of Science Core Collection. By leveraging VOSviewer and bibliometrix tools, we demonstrate that while the USA dominates in publication quantity, the Netherlands commands the highest citation influence, reflecting the enduring legacy of foundational works by Sato and Clevers. Co-citation and keyword trend analyses demonstrate evolving research priorities. The field initially focused on stem cell differentiation and culture optimization, then expanded into disease modeling of colorectal cancer and inflammatory bowel disease. Notably, recent burst detection identifies a clear pivot towards "organ-on-a-chip" technology, "mechanobiology," and "single-cell sequencing". These hotspots signal the advent of precision engineering. Bioengineering and high-throughput omics together drive the development of next-generation physiologically relevant intestinal models. Ideally, this bibliometric blueprint serves as a navigational guide for researchers, highlighting the paradigm shift towards complex, engineered micro-physiological systems (MPS) as the future of intestinal research.
SIRT6 enhances the therapeutic potential of extracellular vesicles in mitigating osteoarthritis in rat models.
Yang G, Liu S, Han H … +11 more , Yang X, Li F, Wu Q, Zhao Z, Liu F, Zheng Z, Gao G, Ma W, Zhao L, Liu B, Wu Z
Stem Cell Res Ther · 2026 Jun · PMID 42337776 · Full text
BACKGROUND: Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapeutic candidates for osteoarthritis (OA). Sirtuin 6 (SIRT6), a class III histone...
BACKGROUND: Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapeutic candidates for osteoarthritis (OA). Sirtuin 6 (SIRT6), a class III histone deacetylase, exerts protective effects by preventing cellular senescence, reducing inflammation, and promoting longevity. This study aims to generate immortalized hUCMSCs with SIRT6 and telomerase reverse transcriptase (TERT) overexpression and investigate the therapeutic potential of their secreted EVs (EVs@SIRT6) in OA. METHODS: hUCMSCs were genetically engineered using lentiviral transduction to overexpress SIRT6 and TERT, referred to as SIRT6/TERT-hUCMSCs. Natural EVs and EVs@SIRT6 were isolated via differential ultracentrifugation and characterized by morphology, size distribution, marker expression, and proteomic signature. Their effects on IL-1β stimulated chondrocytes were assessed in vitro, including cell viability, apoptosis, scratch closure, inflammatory cytokine secretion, and oxidative stress. Transcriptomic alterations were analyzed by RNA sequencing. Therapeutic efficacy in vivo was evaluated in a rat anterior cruciate ligament transection (ACLT) model via micro-computed tomography, histological analyses, and immunohistochemistry. RESULTS: SIRT6/TERT-hUCMSCs preserved mesenchymal identity, trilineage differentiation potential, and sustained proliferative capacity up to passage 60, accompanied by longer telomeres and reduced senescence compared to parental cells. EVs@SIRT6 maintained typical EV features but were enriched in SIRT6 protein and displayed a distinct proteomic signature, comprising 1,440 unique proteins associated with nuclear/chromatin repair. In vitro, EVs@SIRT6 more effectively enhanced chondrocyte viability and wound healing while reducing apoptosis compared with natural EVs. EVs@SIRT6 also markedly alleviated inflammatory response, promoted anabolism, suppressed catabolism, and mitigated oxidative stress in chondrocytes. The protective effects of EVs@SIRT6 on chondrocytes were associated with the suppression of the JAK-STAT signaling pathway. Studies in a rat ACLT model further confirmed that EVs@SIRT6 outperformed natural EVs in attenuating subchondral osteosclerosis, reducing osteophyte formation, and mitigating cartilage damage. CONCLUSIONS: Engineered EVs@SIRT6 outperform natural EVs in preserving chondrocytes homeostasis and reducing OA progression, establishing an efficient platform for preparing engineered EVs for clinical application.
iRGD-modified 3D exosomes delivered miR-99b-5p induces ferroptosis to inhibit colorectal cancer progression by regulating FGFR3/PI3K/AKt pathway.
Li XH, Lian FW, Lv F … +4 more , Luo XL, Hu BL, Zhang LT, Ning SF
Stem Cell Res Ther · 2026 Jun · PMID 42337603 · Full text
BACKGROUND: Mesenchymal stem cells (MSCs)-derived exosomes present great potential as nanocarriers for targeted drug delivery. Moreover, the therapeutic efficacy of exosomes can be substantially enhanced through function...
BACKGROUND: Mesenchymal stem cells (MSCs)-derived exosomes present great potential as nanocarriers for targeted drug delivery. Moreover, the therapeutic efficacy of exosomes can be substantially enhanced through functional modifications and the incorporation of bioactive molecules. METHODS: In this study, the MSCs were cultured under two-dimensional (2D) and three-dimensional (3D) cell culture conditions. The culture supernatants were collected for isolating exosomes. The characteristics and yields of exosomes from 2D and 3D cultures were detected by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), western blot analysis, and bicinchoninic acid (BCA) assay. Subsequently, 3D exosomes were loaded with miR-99b-5p and modified with iRGD peptide were formed into a new engineered exosome, designated as iRGD-Exo-miR-99b-5p. The effects of these engineered exosomes on the progression of colorectal cancer (CRC) were assessed through a series of in vivo and in vitro experiments. RESULTS: The 3D-cultured MSCs exhibited a higher yield of exosomes and enhanced uptake by CRC cells. Further in vitro experiments demonstrated that 3D-exosomes loaded with miR-99b-5p effectively inhibit the proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) of CRC cells. Results from a xenograft tumor model indicate that iRGD-modified exosomes were significantly enriched at tumor sites. Furthermore, exosomes modified with iRGD and loaded with miR-99b-5p were employed for CRC treatment, resulting in substantial tumor growth inhibition and enhanced the chemotherapy efficacy of 5-fluorouracil (5-FU) in vivo, without inducing notable toxicity or side effects. Mechanistically, exosome-mediated delivery of miR-99b-5p downregulated FGFR3 expression, thereby inhibiting the activation of the PI3K/AKt signaling pathway and promoting ferroptosis, ultimately attenuating CRC progression. CONCLUSIONS: Collectively, iRGD-modified 3D exosomes loaded with miR-99b-5p were able to specifically target tumor sites, thereby significantly suppressing CRC growth through the induction of ferroptosis via regulating the FGFR3/PI3K/AKt signaling pathway. These findings suggest that functional engineering and bioactive loading of 3D-exosomes derived from MSCs represent a promising strategy for targeted cancer therapy.
Stem cell-based tactics in the remodeling and treatment of intestinal diseases.
Ren Y, Zhang S, Wang J … +6 more , Wang Y, Xu M, Zhang L, Ge K, Chu Y, Zhang L
Stem Cell Res Ther · 2026 Jun · PMID 42332757 · Full text
Intestinal diseases are imposing a prevalent socioeconomic burden worldwide, which is largely attributed to the disrupted homeostasis of gut-immune crosstalk including gut microbiota dysbiosis and immunomodulatory imbala...
Intestinal diseases are imposing a prevalent socioeconomic burden worldwide, which is largely attributed to the disrupted homeostasis of gut-immune crosstalk including gut microbiota dysbiosis and immunomodulatory imbalance. Stem cells are unique cell populations with self-renewal and multi-lineage differentiation properties, and current literature has indicated the remarkable applications in early embryogenesis, disease remodeling and novel cytotherapy via diverse modes of action (e.g., direct- or trans-differentiation, cytokine paracrine, and bidirectional immunomodulation). Of them, human pluripotent stem cells (hPSCs) and the derivatives, including the self-organizing organoids, have been vastly employed for intestinal disease remodeling, while mesenchymal stem/stromal cells (MSCs) and the microvesicles are adopted for multifarious intestinal disorder intervention. In this review article, we mainly focus on the progressions in stem cell-based disease remodeling (intestinal lineage and organoid induction from hPSCs) and cellular therapy for intestinal diseases (e.g., inflammatory bowel disease, infectious intestinal diseases, and colorectal cancer), together with the underlying repair mechanisms (e.g., target genes and signaling pathways). Furthermore, the promising prospective and the concomitant challenges of stem cell-based preclinical and clinical investigations upon intestinal disorders are also outlined, including ethical considerations and supervision, heterogeneity and standardization, integration with novel biotechnologies (e.g., single-cell RNA sequencing, intracellular tracing, gene-editing and three-dimensional bioprinting). Collectively, our findings will supply profitable references and facilitate the development of stem cell-based mechanistic investigation and regenerative medicine for intestinal diseases.
FDA roadmap to reducing animal testing: a regulatory and scientific paradigm shift in nonclinical safety assessment.
Lei Y, Tuan RS, Li ZA
Stem Cell Res Ther · 2026 Jun · PMID 42324566 · Full text
On April 20, 2026, the U.S. Food and Drug Administration FDA published a 1-year progress report of its initiative to reduce animal testing requirement in drug development. The FDA roadmap, announced on April 10, 2025, re...
On April 20, 2026, the U.S. Food and Drug Administration FDA published a 1-year progress report of its initiative to reduce animal testing requirement in drug development. The FDA roadmap, announced on April 10, 2025, represented a pivotal paradigm shift toward human-centric New Approach Methodologies (NAMs), including stem cell-derived organoids, organs-on-chips, in silico modeling, and AI-enabled tools. The aim is to address the longstanding challenges of conventional preclinical safety assessment using animal models, including poor translational predictability, high cost, ethical concerns, and inherent interspecies biological differences, resulting in high clinical attrition and delayed access to effective therapies. In this commentary, we critically evaluate the scientific rationale, first-year implementation progress, and global regulatory impact of the FDA initiative. We highlight landmark advances including the permanent Innovative Science and Technology Approaches for New Drugs (ISTAND) program, human-centric validation principles, streamlined nonclinical frameworks for biologics, and alignment with global agencies and regulators. We also discuss existing, persistent challenges, such as uneven validation across toxicological endpoints, incomplete global data sharing, and cultural inertia, and propose actionable strategies to accelerate the safe, systematic adoption of NAMs in regenerative medicine and drug development.
Potential role of natural products in veterinary stem cell therapy.
Shojaee A
Stem Cell Res Ther · 2026 Jun · PMID 42324547 · Full text
In veterinary medicine, stem cells therapy is mostly used to treatment of orthopedic condition. Stem cell behavior is shaped by numerous intrinsic and extrinsic factors. Traditional medicinal herbs-long used to prevent a...
In veterinary medicine, stem cells therapy is mostly used to treatment of orthopedic condition. Stem cell behavior is shaped by numerous intrinsic and extrinsic factors. Traditional medicinal herbs-long used to prevent and treat diverse diseases-together with other natural bioactive compounds have attracted increasing interest because of their potential to modulate stem cell function. Many of these agents exhibit antioxidant, anti-inflammatory, anticancer, and anti-apoptotic activities and may support tissue regeneration by enhancing proliferation, differentiation, and migration. Importantly, natural products may offer safer and more cost-effective alternatives to synthetic growth factors in regenerative strategies. Accordingly, this review summarizes recent evidence on medicinal plants, phytochemicals, algal extracts, and related bioactive compounds that influence veterinary stem cells, and discusses their potential applications in regenerative medicine.
Bone marrow mesenchymal stem cell-derived TSG-6 regulates microglial pyroptosis and alleviates bone cancer pain by inhibiting the NLRP3 inflammasome.
Xu D, Jiang M, Ming H … +4 more , Zhang J, Li Y, Wu P, Wen Q
Stem Cell Res Ther · 2026 Jun · PMID 42323611 · Full text
BACKGROUND: The central sensitization mechanism of bone cancer pain is related to neuroinflammation, glial cell activation, and an acidic environment. Among them, the NLRP3 inflammasome is involved in the occurrence of b...
BACKGROUND: The central sensitization mechanism of bone cancer pain is related to neuroinflammation, glial cell activation, and an acidic environment. Among them, the NLRP3 inflammasome is involved in the occurrence of bone cancer pain. Studies have shown that an intrathecal injection of bone marrow mesenchymal stem cells (BMSCs) alleviates bone cancer pain by inhibiting microglial cell activation. Upon inflammatory stimulation, BMSCs produce increased levels of Tumor necrosis factor-α-stimulated gene 6 (TSG-6), which regulates intercellular signaling and inflammatory responses; however, whether the secretion of TSG-6 from BMSCs inhibits NLRP3-mediated microglial pyroptosis to alleviate bone cancer pain is unknown. Therefore, this study aimed to evaluate the analgesic effect of TSG-6 released by BMSCs on bone cancer pain (BCP) and explore its potential mechanisms through in vitro and in vivo experiments. METHODS: In vivo, Walker 256 breast cancer cells were injected into the bone marrow cavity of the left tibia of rats to establish a BCP model. On days 7 and 14 after surgery, intrathecal injections of BMSCs or exogenous recombinant TSG-6 were administered, and the analgesic effects were observed at 2, 4, 8, 24, and 48 h after administration. Spinal cord tissues were collected for Western blotting and immunofluorescence staining to assess the activation of the NLRP3 signaling pathway. In vitro, BV2 microglia were cocultured with BMSCs or recombinant TSG-6, and the same detection methods were performed to evaluate changes in the levels of proteins involved in the NLRP3 signaling pathway. BMSCs transfected with TSG-6-targeting shRNA were intrathecally injected in vivo or cocultured with microglia in vitro to investigate whether TSG-6 is involved in the inhibition of microglial pyroptosis and the inflammatory response mediated by BMSCs to alleviate BCP. RESULTS: BMSC transplantation or treatment with exogenous recombinant TSG-6 significantly improved BCP-related behaviors, inhibited the expression of key proteins in the NLRP3 signaling pathway in spinal dorsal horn microglia in rats, and reduced the release of inflammatory factors. Experiments revealed that coculturing BMSCs with BV2 microglia or treating BV2 cells with exogenous recombinant TSG-6 inhibited the LPS-induced activation of NLRP3 in BV2 cells and regulated microglial pyroptosis. Transfection of BMSCs with TSG-6-targeting shRNA significantly weakened the inhibitory effect on microglial pyroptosis. CONCLUSION: In vivo and in vitro experiments revealed that bone marrow mesenchymal stem cells inhibit the NLRP3 signaling pathway to regulate the pyroptosis of microglia through the secretion of TSG-6, thereby alleviating bone cancer pain.
Amnion-derived mesenchymal stem cells attenuate anti-GBM glomerulonephritis via regulation of neutrophil CD44 expression.
Nozaki T, Fujieda K, Furuhashi K … +16 more , Shimamura Y, Karasawa M, Koshi-Ito E, Watanabe Y, Onogi C, Hattori K, Kato A, Matsumoto J, Kawazoe T, Horinouchi A, Tanaka A, Kim H, Maeda K, Matsuyama M, Yamahara K, Maruyama S
Stem Cell Res Ther · 2026 Jun · PMID 42321945 · Full text
BACKGROUND: Mesenchymal stem cells (MSCs) possess immunomodulatory and tissue repair properties, and their therapeutic efficacy has been reported in models of glomerulonephritis. However, the clinical application of bone...
BACKGROUND: Mesenchymal stem cells (MSCs) possess immunomodulatory and tissue repair properties, and their therapeutic efficacy has been reported in models of glomerulonephritis. However, the clinical application of bone marrow-derived MSCs (BMSCs) is limited due to the invasive nature of bone marrow harvesting. In this study, we focused on amnion-derived MSCs (AMSCs), which can be obtained non-invasively after delivery, and investigated their therapeutic effects in a rat model of anti-glomerular basement membrane (GBM) nephritis. METHODS: In a rat model of anti-GBM nephritis, human AMSCs, BMSCs, or vehicle were intravenously administered. Evaluations included renal function, histology, intravital imaging of glomerular neutrophils, and flow cytometric analysis of leukocytes. In addition, we used an anti-CD44 neutralizing antibody in vivo to examine the therapeutic relevance of CD44 blockade, including its impact on neutrophil. RESULTS: The renoprotective effects observed in the AMSC-treated group were comparable to or greater than those in the BMSC-treated group. Furthermore, neutrophils exposed to AMSCs exhibited shorter dwell time in the glomeruli, and specifically in renal neutrophils, the expression of the adhesion molecule CD44 was reduced. In addition, administration of an anti-CD44 antibody produced similar renoprotective effects and reductions in neutrophil infiltration, suggesting that modulation of CD44 signaling contributes to the renoprotective effects of AMSCs. CONCLUSIONS: Collectively, these findings indicate that AMSCs exert renoprotective effects comparable to or greater than those of BMSCs, and may represent a novel therapeutic approach for anti-GBM nephritis by specifically suppressing CD44 expression in neutrophils at sites of inflammation.
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