Stem Cell Res Ther [JOURNAL]
Sun
200 papers
Tracing the in vivo behavior of nucleated cultured red blood cells generated from hematopoietic stem and progenitor cells.
Xu L, Yang Z, Liang L … +8 more , Zhang J, Yuan X, Liu P, Dong Q, Pei X, Qu M, Yue W, Xie X
Stem Cell Res Ther · 2026 Apr · PMID 41987318 · Full text
BACKGROUND: Red blood cells generated from stem cells, called cultured RBCs (cRBCs), may alleviate the shortage of blood supplies worldwide. The intermediate product, nucleated cRBCs, may further bypass the inconvenience...
BACKGROUND: Red blood cells generated from stem cells, called cultured RBCs (cRBCs), may alleviate the shortage of blood supplies worldwide. The intermediate product, nucleated cRBCs, may further bypass the inconvenience of RBC manufacturing. Elucidating the in vivo behavior of cRBCs, especially the interaction between cRBCs and macrophages, will aid in understanding the effects of their transfusion and facilitate the clinical translation of these cells. METHODS: In this study, we generated large-scale nucleated cRBCs from cord blood mononuclear cells using G-Rex bioreactors and evaluated their in vivo distribution, maturation and function by infusing these cells into irradiated NOD/SCID mice and comparing them with the properties of infused mature human RBCs. RESULTS: Similar to the infusion of mature human RBCs, in the absence of macrophage depletion, the infusion of cRBCs improved the maintenance of the red blood cell count and hemoglobin concentration, but the infused human cells were barely detected in the peripheral blood of the mice. Immature cRBCs accumulated in various organs, including the spleen, bone marrow and liver, at 2 h postinfusion, independent of macrophage depletion. Macrophages phagocytose mature foreign RBCs while nursing immature cRBCs until maturation; the difference in the innate expression of cRBCs during maturation might account for this effect. In the short term after transfusion, the spleen and bone marrow were the major sites of cRBC maturation. In the liver, macrophages primarily functioned to clear mature foreign RBCs. cRBCs matured, enucleated, and were released into the circulation within one to three days after infusion. Pulmonary accumulation of cRBCs and embolism were not observed after the cRBC infusion. CONCLUSIONS: Nucleated cRBCs can mature in vivo, and their transfusion advances our understanding of their potential as future transfusion products.
A systematic review of clinical evidence on the efficacy and safety of conditioned media, platelet-rich fibrin, stromal vascular fraction, extracellular vesicles, and stem cells in androgenetic alopecia.
Behrangi E, Amiri S, Zeinali R … +4 more , Goodarzi A, Roohaninasab M, Khosravi M, Jafarzadeh A
Stem Cell Res Ther · 2026 Apr · PMID 41987228 · Full text
AIMS AND OBJECTIVES: Androgenetic alopecia (AGA) is a common progressive hair loss disorder caused by follicular miniaturization and shortened anagen phases. Conventional treatments mainly target androgen pathways but of...
AIMS AND OBJECTIVES: Androgenetic alopecia (AGA) is a common progressive hair loss disorder caused by follicular miniaturization and shortened anagen phases. Conventional treatments mainly target androgen pathways but often yield unsatisfactory results. Regenerative medicine has emerged as a novel therapeutic approach aiming to restore follicular function through biologically active cell-based or cell-free therapies. This systematic review aimed to evaluate the efficacy and safety of five major regenerative modalities in AGA-conditioned media (CM), platelet-rich fibrin (PRF), stromal vascular fraction (SVF), extracellular vesicles (EV), and stem cells (SCs)-while comparing their outcomes and identifying the most frequently investigated methods, highest response rates, and areas requiring further research. METHODS: This systematic review followed PRISMA guidelines. PubMed, Scopus, and Web of Science were searched for studies published up to September 1, 2025. Eligible studies included patients diagnosed with AGA who received regenerative medicine interventions and reported measurable clinical outcomes. Data were extracted on participant characteristics, intervention type, efficacy outcomes, and adverse events. Risk of bias was assessed using ROB-2 for RCTs and ROB-I for non-randomized studies. RESULTS: A total of 20 clinical studies involving 724 patients were included, encompassing randomized controlled trials, prospective cohorts, case series, pilot studies, and retrospective analyses. Among the included studies, CM was the most extensively investigated therapy (6 studies, 229 patients), showing consistent improvements in hair density (7-16%) and thickness (11-32%), with up to 85% increase in hair count when combined with minoxidil. PRF demonstrated the fastest and most consistent responses, with 62-97% improvements in hair density within 3-6 months and additional benefits when used with hair transplantation. SVF showed comparable or superior outcomes to platelet-rich plasma (PRP), with density increases of 41-48% after a single injection and synergistic effects when combined with PRP or fat grafting. EV therapy, though less studied (3 studies, 89 patients), showed hair count increases of 28% and density gains up to 45% in certain subgroups, with higher responses in early-stage AGA. Stem cell and micrograft therapies (3 studies, 146 patients) demonstrated the strongest regenerative potential, with hair density improvements of 30% within two months, histological evidence of follicle regeneration, and significant quality of life benefits. Across all approaches, only mild, transient adverse events were reported. CONCLUSION: Regenerative medicine offers effective and safe therapeutic options for AGA, with each modality providing distinct advantages. Despite encouraging results, heterogeneity in study protocols and limited long-term data highlight the need for larger randomized controlled trials, standardized methodologies, and extended follow-up to determine the optimal regenerative strategy for AGA.
hucMSCs alleviate LPS-induced endothelial glycocalyx damage by secreting Cxcl12 to activate CXCR4.
Cui J, Peng Z, Chen Y … +6 more , Liu W, Chen Q, Wang X, Wang T, Huang X, Sun T
Stem Cell Res Ther · 2026 Apr · PMID 41987219 · Full text
Acute respiratory distress syndrome (ARDS) has a high clinical mortality rate and continues to draw research attention regarding its mechanisms and potential treatments. Disruption of the endothelial barrier is a primary...
Acute respiratory distress syndrome (ARDS) has a high clinical mortality rate and continues to draw research attention regarding its mechanisms and potential treatments. Disruption of the endothelial barrier is a primary pathological feature, and glycocalyx degradation is a key factor contributing to this disruption. Human umbilical cord mesenchymal stem cells (hucMSCs) exhibit strong anti-inflammatory and immunomodulatory effects, making their application in ARDS treatment an area of increasing interest. Proteomic screening identified Cxcl12 as a protein secreted by hucMSCs. In male C57 mice and cell models, lipopolysaccharide (LPS) was used to induce injury, followed by interventions with hucMSCs or hucMSCs with silenced Cxcl12 to assess glycocalyx-related proteins SDC-1, HS, and the repair marker EXT-1. To evaluate downstream signaling, the CXCR4 receptor was inhibited and related indicators were examined. Silencing Cxcl12 reduced the therapeutic effect of hucMSCs on LPS-induced glycocalyx damage. Inhibition of CXCR4 also weakened the effect of Cxcl12. These findings indicate that hucMSCs alleviate LPS-induced glycocalyx damage in pulmonary vascular endothelial cells by secreting Cxcl12, which activates the downstream receptor CXCR4, providing a therapeutic effect for ARDS.
ATG5 overexpression enhances the therapeutic efficacy of mesenchymal stem cells in a mouse colitis model by augmenting anti-inflammatory and antioxidative mechanisms.
Sun Y, Sun H, Zhao T … +3 more , Zhao Y, Xiao F, Wang L
Stem Cell Res Ther · 2026 Apr · PMID 41981417 · Full text
BACKGROUND: The therapeutic efficacy of mesenchymal stem cells (MSCs) can be improved by enhancing their adaptation to the inflammatory microenvironment. Autophagy maintains MSCs functionality, and autophagy-related gene...
BACKGROUND: The therapeutic efficacy of mesenchymal stem cells (MSCs) can be improved by enhancing their adaptation to the inflammatory microenvironment. Autophagy maintains MSCs functionality, and autophagy-related gene 5 (ATG5) mediates autophagy and regulates the biological functions and therapeutic efficacy of these cells. The aim of this study was to investigate the role of ATG5 in the antioxidant capacity and evaluate the therapeutic effect of ATG5-engineered MSCs for colitis treatment. METHODS: Cell viability was assessed using a Cell Counting Kit-8. The mRNA expression of autophagy-, antioxidant-, and polarization-related genes was determined through real-time quantitative polymerase chain reaction, and protein expression was analyzed via western blotting. Macrophage polarization markers were analyzed using flow cytometry. Multiomics approaches, including RNA transcriptome sequencing, untargeted metabolomics, and 16S ribosomal RNA microbiota analysis, were also used. Mice with dextran sulfate sodium-induced colitis were used to evaluate the therapeutic efficacy of MSCs. RESULTS: Preconditioning MSCs with hypoxia (1% O₂) and serum deprivation significantly enhanced autophagy and upregulated ATG5 expression. Adenovirus-mediated ATG5 overexpression in MSCs (MSCs-ATG5) enhanced their autophagic activity and antioxidant capacity, upregulated HMOX-1, SOD2, and CAT expression, and increased glutathione peroxidase and catalase enzymatic activity, while enhancing cell proliferation, without altering surface marker expression. Further, MSCs-ATG5 significantly promoted M2 macrophage polarization and regulated oxidative stress-related signaling pathways. Additionally, MSCs-ATG5-based therapy markedly ameliorated colitis disease signs in mice. Transcriptome analysis revealed that MSCs-ATG5 suppressed the IL-17/NF-κB inflammatory signaling pathway. This treatment also regulated levels of the anti-inflammatory metabolite prostaglandin D2 (PGD2) in colon tissues. Finally, MSCs-ATG5 increased the abundance of butyrate-producing bacteria (e.g., Oscillospirales), thereby alleviating intestinal microbiota dysbiosis. CONCLUSION: Adenovirus-mediated ATG5 overexpression enhances the autophagic activity, immunomodulatory functions, and antioxidant capacity of MSCs. MSCs-ATG5 can alleviate colitis by inhibiting the IL-17/NF-κB inflammatory signaling pathway, enhancing secretion of the anti-inflammatory metabolite PGD2, and increasing the abundance of butyrate-producing bacteria. Our findings support the potential clinical efficacy of MSCs-ATG5-based therapies.
The metabolic profiles of cancer stem cells.
Tylichova Z, Vojtesek B, Coates PJ
Stem Cell Res Ther · 2026 Apr · PMID 41975495 · Full text
Cancer stem cells (CSCs) represent a minor but highly adaptable subpopulation within tumors that drives long-term growth, metastasis, and therapy resistance. Their ability to survive and regenerate under metabolic and th...
Cancer stem cells (CSCs) represent a minor but highly adaptable subpopulation within tumors that drives long-term growth, metastasis, and therapy resistance. Their ability to survive and regenerate under metabolic and therapeutic stress relies on a unique integration of energy flexibility, redox balance, and proteostatic programs. While bulk tumor cells typically favor aerobic glycolysis and high protein turnover, CSCs often exhibit elevated mitochondrial activity, fatty acid oxidation, and selective suppression of proteasome function. These metabolic features support quiescence, stress tolerance, and self-renewal. Beyond energy production, metabolic intermediates such as acetyl-CoA, succinate, and lactate serve as epigenetic cofactors, linking nutrient availability to chromatin remodeling and transcriptional plasticity. Reactive oxygen species and antioxidant responses further tune this balance, shaping the transition between glycolytic and oxidative CSC states. These intrinsic programs are continuously influenced by the tumor microenvironment, where hypoxia, cytokine-driven signaling, and metabolic coupling with stromal and immune cells modulate CSC metabolism and reinforce stemness. Despite rapid progress, major conceptual and methodological gaps still limit our understanding of CSC metabolism and this review highlights these unresolved issues and further outline key contextual factors-including tumor-intrinsic, microenvironmental, systemic, and metastatic cues-that shape CSC metabolism and help explain the divergent observations reported across studies. Understanding this network will be essential for designing combinatorial therapies that target CSC metabolism while accounting for their heterogeneity and plasticity.
Quercetin-loaded composite materials for bone regeneration: a review of carriers, controlled release, and mechanistic advances.
Zhao X, Ye X, He Y … +4 more , You P, Hsu Y, Liu Y, Dong H
Stem Cell Res Ther · 2026 Apr · PMID 41965753 · Full text
Quercetin is a natural flavonoid with strong antioxidant, anti-inflammatory, and osteogenic effects, showing great promise for bone regeneration. However, its poor solubility, low bioavailability, and rapid degradation l...
Quercetin is a natural flavonoid with strong antioxidant, anti-inflammatory, and osteogenic effects, showing great promise for bone regeneration. However, its poor solubility, low bioavailability, and rapid degradation limit clinical use. Innovative quercetin-loaded composite biomaterials address these challenges by providing precise, controlled release and enhancing therapeutic efficacy. In recent years, quercetin-loaded composite materials have shown significant research progress in the field of bone tissue engineering. Studies indicate that in vitro experiments demonstrate the excellent biocompatibility of these materials, which promote osteogenic differentiation, induce macrophage polarization toward the M2 phenotype, scavenge reactive oxygen species, exert antibacterial effects, and enhance angiogenesis. In vivo studies confirm that quercetin-loaded composite materials increase bone volume, density, and vascularization, with various signaling pathways. This review integrates novel mechanistic insights, addresses challenges like optimal dosing and smart responsiveness, and outlines pathways for quercetin composites in repairing complex bone defects, paving the way for advanced regenerative therapies with strong clinical potential.
The role of mesenchymal stem cells in IgA nephropathy: current evidence and future directions.
Liu Y, Zhao Y, Xie J … +5 more , Chen J, Yao K, Chen W, Zheng L, Zhou T
Stem Cell Res Ther · 2026 Apr · PMID 41965680 · Full text
Primary glomerular disease, particularly IgA Nephropathy (IgAN), is one of the leading causes of kidney disease burden. IgAN is characterized by IgA deposition in the mesangial area; this is a typical pathological featur...
Primary glomerular disease, particularly IgA Nephropathy (IgAN), is one of the leading causes of kidney disease burden. IgAN is characterized by IgA deposition in the mesangial area; this is a typical pathological feature that leads to nephritis symptoms. Though the cause is unknown, the quadripartite attack theory is generally accepted. There are many reasons, but the biggest is an imbalance in the immune system. Recently, some studies have shown that mesenchymal stem cells (MSCs) can regulate IgA production and clearance by controlling B cells, T cells, and mucosal epithelial cells. Currently, the standard treatment for IgAN primarily relies on supportive care and immunosuppression, but these approaches are ineffective and have serious side effects. In contrast, stem cell therapy is a promising option and shows great promise in diagnosing and treating various kidney diseases. This review provides an update on recent advances in IgAN using stem cell therapy, including disease mechanisms, treatment pathways, clinical trials, case reports, safety concerns, current challenges, and prospects.
Apoptotic BMSCs reduce grafted islets apoptosis through the holo-Lcn2/Slc22a17/Fe axis.
Lu C, Wang J, Wang Y … +7 more , Wang J, Bi H, Yu X, Chen Z, Dong B, Ma R, Ding X
Stem Cell Res Ther · 2026 Apr · PMID 41964097 · Full text
Early apoptosis of grafted islets is one of the critical challenges that significantly impact the efficacy of islet transplantation. We employed Staurosporine to pre-induce apoptosis in bone marrow mesenchymal stem cells...
Early apoptosis of grafted islets is one of the critical challenges that significantly impact the efficacy of islet transplantation. We employed Staurosporine to pre-induce apoptosis in bone marrow mesenchymal stem cells (BMSCs). The conditioned medium from apoptotic BMSCs was then used to pretreat β cells, which notably enhanced the suppression of β cell apoptosis. For in vivo experiments, co-transplantation of islets and apoptotic BMSCs under the renal capsule of diabetic rats inhibited islets apoptosis and resulted in better transplantation outcomes. Subsequently proteomic analysis revealed that the iron-loaded form of Lcn2 protein (holo-Lcn2) secreted by apoptotic BMSCs played a crucial role in exerting anti-apoptotic effects. Holo-Lcn2 binds to the Slc22a17 transporter on cell membrane, facilitating the transport of Fe into cells. Inhibition of Fe transport suppressed the anti-apoptotic effect of holo-Lcn2. Thus, we hypothesize that apoptotic BMSCs reduce grafted islets apoptosis through the holo-Lcn2/Slc22a17/Fe axis. This study provides insights into the application of BMSCs-based acellular therapies in islet transplantation.
Defined culture conditions improve functional properties of mature iPSC-derived macrophages for therapeutic screening.
Schinke M, Gensch I, Rietschel T … +4 more , Nguyen AHH, Slevogt H, Jänsch L, Lachmann N
Stem Cell Res Ther · 2026 Apr · PMID 41964059 · Full text
BACKGROUND: Generation and use of human macrophages in vitro are essential for a variety of (therapeutic) applications. Recently, there has been growing interest in macrophages derived from induced pluripotent stem cells...
BACKGROUND: Generation and use of human macrophages in vitro are essential for a variety of (therapeutic) applications. Recently, there has been growing interest in macrophages derived from induced pluripotent stem cells (iPSC-Mac), which has led to the development of numerous differentiation protocols. These protocols typically involve a stepwise differentiation process using well-defined culture media, though the final differentiation stage often relies on undefined animal serum components, such as fetal bovine serum (FBS). This study aimed to elucidate protocol-dependent effects on iPSC-Mac usability. METHODS: We assessed the impact of a serum-supplemented medium (RPMI + FBS) compared to a fully defined medium (X-VIVO 15™) on the function of terminally differentiated human iPSC-Mac. Upon harvest, the cells were differentiated for three to four days in the respective media. Subsequently, phenotypic analysis was performed by microscopy and flow cytometry, as well as transcriptome and proteome analysis. Functional responsiveness to stimuli such as polarizing cytokines and lipopolysaccharide (LPS) was evaluated using flow cytometry and ELISA assay. The pharmaceutical screening potential was examined using secondary stimuli with dexamethasone. RESULTS: While both media compositions effectively produced fully functional human macrophages, we observed significant differences in their stage of activation and their functional responsiveness. Macrophages differentiated under the defined, serum-free conditions showed a more neutral activation state, an enhanced cholesterol metabolism, and were more sensitive to post pro- or anti-inflammatory stimulation compared to serum-grown cells. Most important, iPSC-Mac from these cultures also exhibit a more robust and reproducible response to co-stimulatory signals with IFNγ or LPS in combination with the immune-suppressive agent dexamethasone. In contrast, serum-grown iPSC-Mac demonstrated a more pre-activated state, with noteworthy background levels of interleukin 6 (IL-6). Upon stimulation, these cells showed reduced sensitivity and responsiveness towards secondary signals, underscoring potential challenges when using FBS-based media for drug screening or immunomodulatory assessments. CONCLUSIONS: The enhanced responsiveness to co-stimulatory signals makes iPSC-Mac from defined cultures more suitable for testing immunomodulatory drugs, novel bio-assays and in vivo applications.
Clarifying the critical differences between the enzymatic stromal vascular fraction and the mechanically derived stromal vascular tissue or nanofat for spinal cord injury applications.
Nonnarath C, Serratrice N
Stem Cell Res Ther · 2026 Apr · PMID 41964032 · Full text
This letter aims to address the increasing confusion surrounding the concepts and terminology of enzymatically derived stromal vascular fraction (eSVF) and mechanically processed adipose tissue, which is often referred t...
This letter aims to address the increasing confusion surrounding the concepts and terminology of enzymatically derived stromal vascular fraction (eSVF) and mechanically processed adipose tissue, which is often referred to as stromal vascular tissue (mSVT) or nanofat. Although these products are often presented as equivalent, they differ fundamentally in their biological composition, processing methods and regulatory classification. Enzymatic digestion yields a homogeneous, adipocyte-free cellular suspension, whereas mechanical processing preserves adipocytes, extracellular matrix fragments and tissue architecture. In the context of spinal cord injury, these differences give rise to biologically plausible concerns and procedural constraints, particularly with regard to intramedullary delivery. This work highlights the importance of precise terminology, transparent reporting of methods, and careful regulatory alignment to ensure the safe and scientifically sound translation of clinical applications.
From chemically defined hiPSCs to self-organizing cardiac organoids: current strategies guided by developmental signaling.
Yang H, Zeng Y, Teng Y … +4 more , Zhao Q, Hou M, Cheng Z, Wang X
Stem Cell Res Ther · 2026 Apr · PMID 41963991 · Full text
Cardiovascular research and drug development remain constrained by the limited translational relevance of conventional animal and in vitro cellular models, which represent a major bottleneck in the field. In recent years...
Cardiovascular research and drug development remain constrained by the limited translational relevance of conventional animal and in vitro cellular models, which represent a major bottleneck in the field. In recent years, self-organizing cardiac organoids derived from hiPSCs have emerged as a promising alternative. These organoids recapitulate key aspects of human cardiac development, physiological function, and disease-related features in vitro, thereby providing a powerful platform for mechanistic studies and drug screening. The successful establishment of such systems relies on two critical components. First, chemically defined and xeno-free hiPSC culture systems are essential for ensuring experimental standardization and reproducibility. Second, a comprehensive understanding of key developmental signaling pathways (e.g., Wnt and BMP/Activin) and their precise spatiotemporal regulation is required to enhance the maturation and biomimetic fidelity of three-dimensional cardiac models. In this review, we summarize the progression from standardized hiPSC culture systems to the generation of self-organizing cardiac organoids, with a particular focus on the regulatory mechanisms and engineering strategies underlying core developmental signaling pathways. We further discuss the potential applications of this technology in precision cardiovascular medicine.
Generation of biologically responsive colon-like intestinal tissue patches from human induced pluripotent stem cells using a rapid co-differentiation platform.
Dalleywater W, Predeus AV, Cakir B … +22 more , Mazin P, Vadakekolathu J, Rutella S, Meakin ML, Ritchie AA, Montazid S, Ocaña SC, Holmes N, Wright V, Sang F, Santoni S, Bills A, Sculthorpe D, Elmentaite R, Teichmann SA, Irshad S, Tomlinson I, Silver A, Wildman RD, Hannan NRF, Rose FRAJ, Ilyas M
Stem Cell Res Ther · 2026 Apr · PMID 41957847 · Full text
The intestinal mucosa is a complex functional layer which is formed from a diverse range of cell types that include epithelial cells (within crypts and villi) and an array of mesenchymal cells. Many intestinal diseases i...
The intestinal mucosa is a complex functional layer which is formed from a diverse range of cell types that include epithelial cells (within crypts and villi) and an array of mesenchymal cells. Many intestinal diseases involve loss of the surface mucosa which can be difficult to restore, and which delays healing and return to normal function. We reason that development of a transplantable intestinal mucosal tissue graft may be a potential therapeutic strategy to aid healing. To be clinically useful, such a tissue graft would need to be capable of rapid production, avoid the risk of host rejection and be demonstrably safe. To create a potential intestinal graft, we developed a novel early-stage human induced pluripotent stem cell (hiPSC) co-differentiation platform capable of generating multiple intestinal cell lineages (epithelial, mesenchymal and endothelial) in 8 days. This protocol is simple to implement, serum-free and greatly reduces the use of animal products. We confirmed the identity of cells by demonstrating that these cells had RNA and protein expression profiles typical of intestinal cell lineages. In particular, we used bulk and single-cell RNA sequencing to characterise global cellular transcriptional profiles robustly and showed that the cells have intestinal identity with early polarisation towards colonic differentiation. The results were replicated across multiple hiPSC lines and in an independent centre. We further cultured the derived cells on collagen hydrogels to form colon-like intestinal patches (CL-IPs). When transplanted into mouse subcutis, CL-IPs formed into colon-like tissue structures, including crypts, stromal and muscle layers. They also developed human-origin vasculature which underwent anastomosis with the murine vasculature to transport murine blood into the graft. Teratoma assays and molecular analyses showed no evidence of residual pluripotency. While at an early stage, this platform shows great potential for further development as a potential source for novel intestinal mucosal regeneration therapy. In addition, the platform is physiologically relevant and thus shows promise as the basis for a new generation of in vitro models of intestinal pathobiology.
Transcriptomic and functional comparison of adipose-and bone marrow-derived mesenchymal stem cells for tendon regeneration.
Khaled H, Zayed M, Kim B … +2 more , Jeong BH, Oh SI
Stem Cell Res Ther · 2026 Apr · PMID 41957779 · Full text
BACKGROUND: Tendons are specialized connective tissues with limited intrinsic healing properties due to hypovascularity and low metabolic activity. Mesenchymal stem cells (MSCs) possess regenerative potential for tendon...
BACKGROUND: Tendons are specialized connective tissues with limited intrinsic healing properties due to hypovascularity and low metabolic activity. Mesenchymal stem cells (MSCs) possess regenerative potential for tendon injuries. Among the diverse sources of MSCs, those derived from the bone marrow (BM-MSCs) and adipose tissue (AD-MSCs) are the leading candidates. However, their relative efficacy remains underexplored, particularly in terms of biological characteristics and tenogenic differentiation. In addition, the signaling pathways driving tenogenic differentiation processes remain poorly understood. This study aimed to comprehensively investigate the regenerative potential of AD-MSCs and BM-MSCs for tendon repair. METHODS: AD- and BM-MSCs were isolated from rats and evaluated for stemness based on morphology, viability, immunophenotyping, and tri-lineage differentiation. RNA sequencing was performed to obtain a baseline molecular profile of each MSC type prior to tenogenic differentiation. We evaluated the potential of AD- and BM-MSCs to differentiate into tendon-like cells in vitro using gene expression and immunofluorescence. A rat model of Achilles tendon injury was created to evaluate the regenerative efficacy following each MSC-type injection. After 6 weeks, tendon regeneration was assessed using histological and immunohistochemical analyses. RESULTS: Both MSCs displayed similarities in morphology, immunophenotyping, and tri-lineage differentiation capacity. AD-MSCs exhibited a superior proliferation rate and tenogenic differentiation compared with BM-MSCs in vitro. Transcriptomic profiling revealed that AD-MSCs significantly upregulated genes related to extracellular matrix remodeling (COL1, TN-C), immunoregulation (IL-33), and tenogenic signaling (FGF18, TGF-β1). AD-MSCs were also enriched in the PI3K-Akt signaling, MAPK signaling, and focal adhesion pathways, indicating enhanced regenerative and tenogenic potential compared to BM-MSCs. Moreover, our data show that AD-MSCs were more effective than BM-MSCs in improving collagen organization and COL1 expression in an animal model of tendon injury. CONCLUSION: Our findings not only highlight the superior regenerative potential of AD-MSCs for tendon repair but also provide a basis for future mechanistic and therapeutic advancements in regenerative medicine.
Isorhamnetin-preconditioned MSC-derived exosomes restore ovarian function by inhibiting ferroptosis in chemotherapy-induced POF.
Zhang Q, Yu J, Zheng Y … +2 more , Jiang J, Zheng L
Stem Cell Res Ther · 2026 Apr · PMID 41947243 · Full text
BACKGROUND: Chemotherapy-induced premature ovarian failure (POF) is a major cause of infertility, with limited treatment options. Mesenchymal stem cell-derived exosomes (MSC-Exos) have therapeutic potential. This study i...
BACKGROUND: Chemotherapy-induced premature ovarian failure (POF) is a major cause of infertility, with limited treatment options. Mesenchymal stem cell-derived exosomes (MSC-Exos) have therapeutic potential. This study investigated whether preconditioning MSCs with the antioxidant flavonoid isorhamnetin (ISO) enhances the efficacy of their exosomes (ISO-MSC-Exos) against POF. METHODS: A cyclophosphamide-induced POF rat model was established, and the role of the ferroptosis inhibitor ferrostatin-1 was evaluated. MSC-Exos and ISO-MSC-Exos were isolated by ultracentrifugation and administered via tail vein injection. Ovarian recovery was assessed by monitoring the oestrous cycle, serum hormone levels, and histological findings. Lipid peroxidation and iron metabolism were evaluated by quantifying malondialdehyde, glutathione, iron deposition, and mitochondrial ultrastructure. Immunohistochemistry was used to assess the expression levels of GPX4, ACSL4, and FTH1. Proteomic analyses were performed to explore the underlying mechanisms. RESULTS: Ferroptosis plays a pivotal role in the cyclophosphamide-induced POF rat model. Both exosome therapies improved ovarian function and suppressed ferroptosis, with ISO-MSC-Exos showing superior efficacy. ISO-MSC-Exos significantly restored hormone levels, ameliorated oestrous cycle disorders, reduced follicular atresia, and enhanced fertility. Furthermore, ISO-MSC-Exos more effectively elevated glutathione levels, reduced malondialdehyde and Fe⁺ levels, and reversed the abnormal expression of ferroptosis-related proteins GPX4, ACSL4, and FTH1. Proteomic analysis suggested that ISO-MSC-Exos effectively inhibit ferroptosis by downregulating Alox15 and Tf, thereby reducing lipid peroxidation substrates and cellular iron uptake. This finding represents a potential molecular mechanism underlying their superior efficacy compared with that of MSC-Exos. CONCLUSIONS: ISO-MSC-Exos showed superior efficacy compared with MSC-Exos in restoring ovarian function and inhibiting ferroptosis, suggesting that ISO pretreatment enhances the therapeutic effect of MSC-Exos in the POF model. Proteomic data provided supportive mechanistic insights into this enhanced efficacy, with the key pathways identified requiring subsequent functional validation.
Innovative strategies for immune thrombocytopenia treatment: immunomodulatory mechanisms and clinical potential of mesenchymal stem cells.
Zhou X, Shan N
Stem Cell Res Ther · 2026 Apr · PMID 41947170 · Full text
Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by increased platelet destruction and impaired megakaryopoiesis within a dysregulated bone marrow niche. Conventional therapies often ach...
Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder characterized by increased platelet destruction and impaired megakaryopoiesis within a dysregulated bone marrow niche. Conventional therapies often achieve only transient platelet recovery, failing to restore immune tolerance, thereby underscoring the need for mechanism-based therapeutic strategies. Mesenchymal stem cells (MSCs) have emerged as promising candidates due to their ability to modulate immune responses and repair the hematopoietic microenvironment. This review synthesizes current evidence regarding the biological properties, immunomodulatory mechanisms, and therapeutic applications of MSCs in ITP, emphasizing intrinsic abnormalities of patient-derived MSCs and the corrective potential of exogenous MSCs from distinct tissue sources. It further integrates emerging insights into MSC functional heterogeneity, optimization of culture conditions, priming strategies, and cellular engineering approaches that may enhance therapeutic efficacy and safety. By highlighting the interplay between immune tolerance restoration and bone marrow niche remodeling, this review provides a translational framework that links mechanistic understanding to the future clinical development of MSC-based therapies for ITP.
Immune-evasive stem cells: engineering tolerance and reprogramming microenvironments for regenerative therapy.
Wu X, Jin S, Pan Y … +10 more , Zhen W, Yu S, Zhang Y, Xu F, Wang R, Wu M, Sun W, Xu J, Zang X, Zhang H
Stem Cell Res Ther · 2026 Apr · PMID 41937145 · Full text
Stem cell transplantation (SCT) holds significant promise for regenerative medicine, yet immune rejection remains a major obstacle. To address this, recent advances leverage CRISPR/Cas9 to engineer hypoimmunogenic induce...
Stem cell transplantation (SCT) holds significant promise for regenerative medicine, yet immune rejection remains a major obstacle. To address this, recent advances leverage CRISPR/Cas9 to engineer hypoimmunogenic induced pluripotent stem cells. These modified cells lack classical immune recognition markers (HLA class I/II) yet retain immune-tolerant molecules such as HLA-E, HLA-G, and CD47, enabling their universal use across different individuals. Additionally, mesenchymal stem cell-derived exosomes and immune checkpoint modulators (e.g., PD-L1) have shown clinical effectiveness by reducing graft-versus-host disease and autoimmune reactions. They achieve this through mechanisms such as suppressing inflammatory T-cell activation, promoting regulatory T-cell expansion, and modulating macrophage polarization. Despite these advances, several challenges remain. One key concern is the potential tumorigenic risk caused by genomic instability during genome editing and long-term cell expansion. Emerging precision editing platforms, including base editing and prime editing, provide strategies to reduce double-strand DNA break-induced chromosomal rearrangements and improve genomic safety. Future research priorities include integrating AI-based immune profiling, precision genome editing, and advanced 3D-bioprinting technologies. Together, these innovations represent a paradigm shift toward developing safer, more effective, universally compatible stem cell therapies for diseases previously deemed untreatable.
Bridging biomaterials and immunotherapy: hydrogel strategies for next-generation CAR-T cell treatment.
Shojaei S, Sani M, Azarpira N … +2 more , Latifi M, Sani F
Stem Cell Res Ther · 2026 Apr · PMID 41928316 · Full text
Breast cancer remains a leading cause of cancer-associated mortality worldwide, with an increasing incidence among younger women, particularly in developing regions and immigrant populations. Although advances in diagnos...
Breast cancer remains a leading cause of cancer-associated mortality worldwide, with an increasing incidence among younger women, particularly in developing regions and immigrant populations. Although advances in diagnostics and targeted therapies have improved patient outcomes, the search for more effective and less toxic treatments continues. Chimeric antigen receptor (CAR) T-cell therapy has transformed cancer immunotherapy by harnessing the body's own immune system to fight malignancy, yet its full potential in solid tumors is still being realized. Meanwhile, hydrogel-based biomaterials have emerged as versatile platforms capable of local immune modulation, sustained cytokine delivery, and enhanced T-cell activation within the tumor microenvironment. By bridging materials science with tumor immunology, this evolving field offers a new perspective on how to direct immune activity precisely where it is needed. Combining hydrogel technology with CAR-T cell therapy represents a promising strategy to strengthen antitumor responses and improve treatment precision and safety.
Retraction Note: Adipose tissue-derived stem cells suppress hypertrophic scar fibrosis via the p38/MAPK signaling pathway.
Li Y, Zhang W, Gao J … +12 more , Liu J, Wang H, Li J, Yang X, He T, Guan H, Zheng Z, Han S, Dong M, Han J, Shi J, Hu D
Stem Cell Res Ther · 2026 Mar · PMID 41913244 · Full text
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Peptide-based Wnt signal activation enables scalable production of clinical-grade patient-derived intestinal organoids for regenerative cell therapy.
Sugihara HY, Nagata S, Kawasaki S … +12 more , Takahashi J, Hiraguri Y, Fukuda M, Suzuki K, Murano T, Fujii S, Fujii T, Shimizu H, Ohtsuka K, Watanabe M, Okamoto R, Mizutani T
Stem Cell Res Ther · 2026 Mar · PMID 41906165 · Full text
BACKGROUND: Gastrointestinal diseases often involve cellular damage, degeneration or dysfunction in the tract, frequently requiring surgical interventions risking complications and lowered quality of life. Regenerative m...
BACKGROUND: Gastrointestinal diseases often involve cellular damage, degeneration or dysfunction in the tract, frequently requiring surgical interventions risking complications and lowered quality of life. Regenerative medicine holds great promise in improving patient care and providing novel treatment options for previously irreparable and untreatable tissues. Despite the clinical potential of intestinal organoids as a resource for regenerative cell therapy and bioengineering, the lack of clinical-grade cultures has hampered further development. Moreover, strategies to efficiently and reliably expand clinical-grade cultures at the scale required for application is limited. METHODS: A GMP-compliant protocol was developed to generate patient-derived colonic organoids from endoscopic biopsies. Clinical-grade colonic organoids cultured and expanded in Type-I collagen were compared to conventional Matrigel cultured organoids. To improve the culture-, cost-, and time-efficiency of culture expansion, several strategies were developed including organoid area-based passaging, one well plate culture, and the incorporation of Wnt activating peptide, PG-008. Conventional recombinant WNT3A culture was compared to the peptide PG-008 culture using single cell RNA sequencing. RESULTS: Clinical-grade collagen cultured organoids exhibited similar culture efficiency to Matrigel. Organoid establishment rate from 60 patients using the GMP-compliant protocol was 82%. The incorporation of PG-008 significantly enhanced organoid growth and stabilized patient-patient variability through intestinal stem cell (ISC) enrichment. Single cell RNA sequencing revealed that PG-008 resulted in remarkably pure culture consisting of ISCs and transit amplifying cells, suitable for rapid and consistent expansion. Intriguingly, our GMP-grade colonic organoids contained LGR5 ISCs, and injury-induced LGR5 regenerative ISCs, both enriched in peptide culture. CONCLUSIONS: Our study establishes clinical-grade colonic organoids for further application, including autologous transplantations and bioengineering. Further, collagen cultured organoids can be a valuable model facilitating in vitro investigations into regenerative stem cell induction and intestinal regeneration.
Mesenchymal stem cell-derived extracellular vesicles in the treatment of type 2 diabetes and its complications: current progress and future directions.
Zhang S, Zhang ZY, Tang RN … +7 more , Zhang K, Fu Y, Tian H, Ma J, Jin Y, Zheng CX, Sui BD
Stem Cell Res Ther · 2026 Mar · PMID 41906148 · Full text
Type 2 diabetes (T2D) and its complications represent a complex disorder involving multiple pathophysiological processes. Although conventional therapeutic approaches partially regulate blood glucose, they fail to fundam...
Type 2 diabetes (T2D) and its complications represent a complex disorder involving multiple pathophysiological processes. Although conventional therapeutic approaches partially regulate blood glucose, they fail to fundamentally reverse disease progression or effectively prevent complications. This review summarizes the current research advance and challenges of using different forms of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in treating T2D and complications. It begins with an introduction to the characteristics of MSC-EVs. Subsequently, the mechanisms and therapeutic prospects of natural MSC-EVs are analyzed, with a focus on their roles in inflammatory modulation, tissue regeneration, and improving insulin resistance. Engineering MSC-EVs, covering strategies including optimizing MSC culture conditions, modifying EV contents, and establishing MSC-EV delivery systems based on bioactive materials are then discussed, which boost EV yield and quality while enhancing therapeutic efficacy. Current challenges, including the limited yield and high heterogeneity of natural MSC-EVs, as well as issues related to long-term safety, immunocompatibility, and large-scale production of engineered MSC-EVs are finally overviewed, with emphasizing artificial intelligence in guiding future research directions. These summaries are crucial for clinical translation of MSC-EVs and will ultimately provide T2D patients with an effective and safe treatment option.
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