Stem Cell Res Ther [JOURNAL]
Sun
200 papers
Senescence modulated cardiac repair with pluripotent stem cell-derived cardiomyocytes.
Zhao J, Kadota S, Ichimura H … +10 more , Yang X, Kusabuka H, Kobayashi H, Kitaori Y, Takahashi H, Omar ZG, Caruso A, Tanaka Y, Shiba N, Shiba Y
Stem Cell Res Ther · 2026 Jun · PMID 42271510 · Full text
BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer great promise for treating heart failure. However, their clinical application remains limited owing to poor cell engraftment, highl...
BACKGROUND: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offer great promise for treating heart failure. However, their clinical application remains limited owing to poor cell engraftment, highlighting the need for scalable production methods that preserve therapeutic efficacy. Although in vitro expansion using glycogen synthase kinase 3β (GSK3β) inhibitors can substantially increase hiPSC-CM yield, the therapeutic potential of these expanded cells is yet to be fully characterized. METHODS: hiPSCs were differentiated into non-expanded cardiomyocytes (N-CMs) via a conventional monolayer protocol or were further replated and cultured with CHIR99021 to generate expanded cardiomyocytes (E-CMs). Both E-CMs and N-CMs were transplanted into a rat myocardial infarction model to evaluate engraftment efficiency. To prevent senescence in E-CMs, cells were treated with the PAPD5 inhibitor BCH001 (E-CM-B) or DMSO as a control (E-CM-D) and then transplanted in the same manner. In vitro, cellular characteristics, including senescence and maturation, were evaluated by adhesion assays, immunocytochemistry, RNA-sequencing (RNA-seq) analysis, and mitochondrial assays. In vivo, cardiac function was assessed by echocardiography, engraftment was monitored via bioluminescent imaging, and the properties of engrafted cells were examined through histological and immunohistochemical analyses. RESULTS: Although GSK3β inhibitor-mediated expansion increased hiPSC-CM yield, it induced telomere shortening, elevated DNA damage, and upregulation of senescence-associated markers, ultimately compromising engraftment and functional recovery after transplantation. Treatment with BCH001 during expansion attenuated senescence markers and promoted mitochondrial maturation. Transplantation of these pharmacologically rescued hiPSC-CMs significantly improved outcomes in infarcted hearts, including increased graft size, enhanced left ventricular function, reduced fibrosis, and promoted in vivo maturation. CONCLUSIONS: This study identifies cellular senescence as a major barrier to the therapeutic efficacy of expanded hiPSC-CMs. Transient pharmacological intervention with a PAPD5 inhibitor during in vitro expansion effectively restores hiPSC-CMs, preserving their regenerative potential. These findings establish a scalable, clinically relevant strategy to overcome current limitations in hiPSC-CM therapy, paving the way for safer and more effective cell-based treatments for heart failure.
Retraction Note: Hurdles to breakthrough in CAR T cell therapy of solid tumors.
Marofi F, Achmad H, Bokov D … +9 more , Abdelbasset WK, Alsadoon Z, Chupradit S, Suksatan W, Shariatzadeh S, Hasanpoor Z, Yazdanifar M, Shomali N, Khiavi FM
Stem Cell Res Ther · 2026 Jun · PMID 42271419 · Full text
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Temporal dynamics of substance P and its association with cytokine release syndrome after CD19 CAR-T therapy in pediatric B-ALL.
Molinos-Quintana Á, Rodríguez-Gil A, Caballero-Velázquez T … +9 more , García-Guerrero E, Alcalde-Mellado P, Hernández-Díaz P, Delgado-Serrano J, Ruiz-Maldonado V, Muñoz-García R, Reguera-Ortega JL, Sánchez-Valderrábanos E, Pérez-Simón JA
Stem Cell Res Ther · 2026 Jun · PMID 42265809 · Full text
BACKGROUND: Cytokine Release Syndrome (CRS) remains a major toxicity associated with chimeric antigen receptor T (CAR-T) cell therapy, particularly in pediatric patients. Although neuroimmune mediators have been implicat...
BACKGROUND: Cytokine Release Syndrome (CRS) remains a major toxicity associated with chimeric antigen receptor T (CAR-T) cell therapy, particularly in pediatric patients. Although neuroimmune mediators have been implicated in systemic inflammation, the role of neuropeptides such as Substance P (SP) in CRS has not yet been explored in this setting. METHODS: Plasma SP levels were measured using an enzyme-linked immunosorbent assay (ELISA) and analyzed longitudinally at predefined time points (day - 1, +7, + 14, and + 28) and during CRS when additional samples were available in 18 pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with CD19 CAR-T therapy (tisagenlecleucel) in a real-world clinical setting. SP dynamics were correlated with severity of CRS, inflammatory biomarkers, and CD19 CAR-T expansion kinetics. RESULTS: Baseline SP levels were similar between patients who developed severe CRS (grade ≥ 3) and those with non-severe CRS. In contrast, the increase in SP levels from baseline (ΔSP) was significantly higher in patients who developed severe CRS (1523 pg/mL vs. 189 pg/mL, p = 0.01). A peak in SP levels was observed at the onset of severe CRS in all three patients, coinciding with the beginning of clinical toxicity and occurring shortly before the elevation in ferritin levels. In these three cases, IL-6 levels increased in close temporal proximity to the rise in SP at the time of maximum CRS severity. Overall, SP levels declined by day + 14 post-infusion, shortly after the peak of CAR-T expansion. This decline coincided temporally with the administration of anti-CRS treatment in the subset of patients with severe CRS. SP levels later increased toward the end of the observation period (around day + 28), approaching baseline values. CONCLUSIONS: These findings suggest that SP dynamics may be linked to the early inflammatory response during CRS and support further investigation of the SP-NK1 receptor axis as a potential therapeutic target to modulate CD19 CAR-T-related toxicity.
Human stem cell models in cerebral cavernous malformations.
Wang Q, Sun J, Zhu X … +2 more , Yu T, Xiao X
Stem Cell Res Ther · 2026 Jun · PMID 42265707 · Full text
Cerebral cavernous malformation (CCM) is a rare cerebrovascular disorder characterized by abnormal endothelial architecture and clinically manifests as hemorrhage, epilepsy, and neurological deficits. Two primary factors...
Cerebral cavernous malformation (CCM) is a rare cerebrovascular disorder characterized by abnormal endothelial architecture and clinically manifests as hemorrhage, epilepsy, and neurological deficits. Two primary factors have constrained the advancement of research in the field of CCM. Firstly, the utilization of animal models, which do not fully recapitulate human neurovascular biology, has been a major impediment. Secondly, the restricted access to patient lesion tissue has hindered progress. These constraints impede mechanistic dissection and therapeutic translation. This review discusses how models derived from human pluripotent stem cells (hPSCs), particularly induced pluripotent stem cells (iPSCs), are advancing research on cardiovascular endothelial cells by enabling human-specific and patient-tailored disease modeling. These stem cell models complement classical mouse models, creating a synergistic approach. The following section summarizes recent advances in three key areas: disease etiology, model development, and translational applications. In particular, the iPSC-derived endothelial cell system has provided mechanistic insights into how mutations in CCM1/2/3 and PIK3CA disrupt endothelial homeostasis in both two-dimensional and three-dimensional contexts, leading to aberrant activation of downstream signaling pathways. The discussion extends to more advanced platforms, including vascular organoids and blood-brain barrier models that more faithfully recapitulate the neurovascular microenvironment and pathological cell-cell interactions. Furthermore, iPSC-based high-throughput drug screening facilitates target validation, drug repurposing, and the development of personalized therapeutic strategies. Although challenges remain regarding model maturity and standardization, stem cell-derived vascular models provide a robust framework for CCM research. This review provides a concise overview of the fundamental iPSC models frequently employed in CCM research and proposes a hierarchical mechanistic framework of "mutation-driven, signal amplification, and lesion evolution." The advantages of 2D and 3D iPSC models for elucidating early endothelial abnormalities, cell-cell interactions, and tissue-level lesion formation are highlighted, and the applicability of various models for reconstructing the CCM microenvironment is emphasized. In conclusion, a model selection strategy for translational research is proposed: iPSC models should be used to elucidate human-derived mechanisms and for drug screening, while animal and chimeric models should be employed to study long-term disease progression, immune involvement, and in vivo validation.
A standardized protocol for autologous stromal vascular fraction therapy in refractory thin endometrium and a prospective single-arm clinical study.
Peng T, Yang S, Fu L … +6 more , Liang L, Liu F, Chen Y, Lian W, Yu Y, Li R
Stem Cell Res Ther · 2026 Jun · PMID 42260663 · Full text
BACKGROUND: Thin endometria are still a big obstacle in fertility treatments and often lead to poor pregnancy outcomes. Stromal vascular fraction (SVF) therapy has shown promise in the improvement of endometrial thicknes...
BACKGROUND: Thin endometria are still a big obstacle in fertility treatments and often lead to poor pregnancy outcomes. Stromal vascular fraction (SVF) therapy has shown promise in the improvement of endometrial thickness. However, its preparation and treatment protocols lack standardization, and its efficacy and safety in assisted reproductive technology (ART) need to be further investigated. METHODS: Through the collaboration of plastic surgery, obstetrics and gynecology as well as Good Manufacturing Practice (GMP) laboratory teams, an efficient protocol was developed for the completion of liposuction, hysteroscopy, SVF preparation, quality control and intrauterine infusion on the same day of treatment. This single-center, prospective, self-controlled prospective cohort study was performed at Peking University Third Hospital. Eligible participants (aged 20-45) were patients who had an endometrial thickness of < 7 mm on the day of ovulation or endometrial transformation in hormone replacement cycles. The primary outcome was the proportion of patients whose endometrial thickness increased to 7 mm. All participants were followed up during the first three menstrual cycles after treatment via hospital follow-up visits and then by telephone for the next two years. All adverse events related to the operation were recorded. Outcomes, including menstrual volume, endometrial thickness, pregnancy rate and offspring health, were measured. This study was registered with Chinese Clinical Trial Registry (ChiCTR), ChiCTR2000035126. RESULTS: Standard SVF preparation and treatment procedures can be efficiently completed within six hours. From December 4, 2020 to August 5, 2022, 35 patients were treated with SVF intrauterine perfusion, and 30 were followed up after the intervention. Participants were aged 35.6 ± 3.85 on average. They had a mean body mass index (BMI) of 24.88 ± 2.05 kg/m2 and a mean pre-treatment endometrial thickness of 5.1 ± 0.94 mm. The SVF used for treating patients had a cell viability of over 90%. After SVF therapy, the mean endometrial thickness at three cycles after treatment was 5.8 ± 0.85 mm, 6.9 ± 1.33 mm and 6.8 ± 1.68 mm, respectively, with a significant increase compared with pre-treatment thickness (p < 0.05). At three months, 18 (51%) of 35 patients achieved an endometrial thickness of 7 mm or above. This increased to 21 (60%) patients two years later. Notably, 11 participants conceived, among whom six gave birth. No adverse events were reported. CONCLUSIONS: A streamlined and efficient protocol was established for SVF preparation and treatment, which ensured the effective patient management and consistent production of high-quality SVF. Autologous SVF intrauterine infusion is promising as a safe and effective therapeutic option for patients with refractory thin endometrium. The absence of adverse effects within this cohort over the two-year follow-up period indicates a good safety profile for SVF therapy.
Mesenchymal stromal cell therapy for systemic lupus erythematosus: mechanisms, clinical translation, and future directions.
Ding S, Wu S, Cui Y … +6 more , Zhou Y, Qiu S, Ye Z, Ma R, Wan YW, Ying Z
Stem Cell Res Ther · 2026 Jun · PMID 42244005 · Full text
Systemic Lupus Erythematosus (SLE) is a complex autoimmune condition, fundamentally characterized by the loss of self-tolerance. This breakdown leads to the generation of autoantibodies and widespread inflammation that c...
Systemic Lupus Erythematosus (SLE) is a complex autoimmune condition, fundamentally characterized by the loss of self-tolerance. This breakdown leads to the generation of autoantibodies and widespread inflammation that compromises multiple organs. A significant clinical challenge in SLE management is the lack of effective options for refractory disease, driving the pursuit of innovative treatments. Among these, mesenchymal stromal/stem cells (MSCs) have garnered significant attention due to their potent immunomodulatory and tissue-repair capabilities, highlighting their potential as a viable therapy. This review critically assesses the potential of MSCs in reconciling the unmet need for effective SLE therapies by examining their immunomodulatory mechanisms, clinical efficacy, and safety. MSCs reestablish immune tolerance through coordinated interactions with T and B cells, macrophages, and dendritic cells, predominantly facilitated by soluble factor secretion and extracellular vesicle release. In severe SLE, allogeneic MSC transplantation has demonstrated a capacity to induce durable remission, restore organ function, and improve survival rates, coupled with a reassuring safety profile. However, the field must still address issues of product standardization and long-term safety evaluation. Next-generation solutions-featuring engineered MSCs, iPSC-MSCs products, and vesicle-based therapies-hold the potential to usher in a new era of personalized SLE treatment. The conduct of large-scale randomized controlled trials is now imperative to definitively establish therapeutic efficacy and optimize clinical protocols.
Extracellular vesicles derived from stem cells of human exfoliated deciduous teeth alleviate pulpitis through attenuation of mitochondrial dysfunction.
Mu Q, Lu H, Li P … +5 more , Wang B, Lin L, Chen Y, Yu D, Zhao W
Stem Cell Res Ther · 2026 Jun · PMID 42243964 · Full text
BACKGROUND: Pulpitis is an inflammatory condition of the dental pulp, in which excessive immune responses and mitochondrial dysfunction are implicated. Extracellular vesicles (EVs) derived from stem cells of human exfoli...
BACKGROUND: Pulpitis is an inflammatory condition of the dental pulp, in which excessive immune responses and mitochondrial dysfunction are implicated. Extracellular vesicles (EVs) derived from stem cells of human exfoliated deciduous teeth (SHED) have shown potential in modulating inflammation, yet the underlying mechanisms remain unclear. This study aimed to investigate whether SHED-EVs attenuate mitochondrial dysfunction in dental pulp stem cells (DPSCs) and thereby alleviate pulpitis. METHODS: SHED-EVs were isolated by ultracentrifugation and characterized. Inflammatory DPSCs (iDPSCs) were induced by lipopolysaccharide (LPS) treatment. The effects of SHED-EVs on proliferation and migration of DPSCs and iDPSCs were assessed using CCK-8, EdU, wound healing, and transwell assays. Inflammation, apoptosis, and mitochondrial function were evaluated by qRT-PCR, ELISA, Western blot, flow cytometry, and mitochondrial assays. RNA sequencing and bioinformatics analyses were performed to identify key regulatory pathways. In vivo, a rat pulpitis model was established, and the therapeutic efficacy of SHED-EVs was assessed by histological and immunohistochemical analyses. RESULTS: SHED-EVs were efficiently internalized by DPSCs and enhanced their proliferation and migration capacities. In iDPSCs, SHED-EVs significantly suppressed the expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, and alleviated cell apoptosis with reduction of cleaved caspase-3 levels and upregulation of Bcl-2. Notably, SHED-EVs decreased mitochondrial reactive oxygen species (mtROS), improved mitochondrial membrane potential (MMP), and increased mitochondrial length. Transcriptomic and Western blot analyses revealed that SHED-EVs modulated inflammatory signaling pathways by inhibiting NF-κB p65 phosphorylation, downregulating NLRP3, and enhancing FoxO1 expression. Furthermore, SHED-EVs alleviated inflammatory infiltration, with reduced IL-1β and IL-6 expression and restored FoxO1 activity in inflamed rat pulp tissue. CONCLUSIONS: SHED-EVs alleviate pulpitis by mitigating mitochondrial dysfunction, potentially through modulation of the NF-κB and FoxO1 pathways. These findings suggest that SHED-EVs have significant anti-inflammatory potential and may represent promising candidates for pulpitis treatment.
L-DOPA enhances iRPE differentiation via Wnt signaling and improves cytotherapy for retinal degradation.
Ke Y, Zhao Y, Feng Q … +4 more , Xue M, Zhang M, Tan L, Ren X
Stem Cell Res Ther · 2026 Jun · PMID 42231481 · Full text
BACKGROUND: Transplantation of stem cell-derived Retinal Pigment Epithelium (RPE) cells offers significant therapeutic potential for treating retinal degenerative diseases (RDDs). To enhance the efficacy and safety of su...
BACKGROUND: Transplantation of stem cell-derived Retinal Pigment Epithelium (RPE) cells offers significant therapeutic potential for treating retinal degenerative diseases (RDDs). To enhance the efficacy and safety of such cell replacement therapies, it is essential to efficiently generate high-quality RPE donor cells. The crosstalk between dopamine signalling and the Wnt pathway provides an important mechanism underlying RPE cell fate determination during eye development. METHODS: We present a protocol for RPE differentiation from iPSCs with L-DOPA supplementation. The effect of L-DOPA is attributed to the activation of Wnt signalling, mediated through the dopamine D1 receptor, which triggers the downstream cAMP/PKA signalling cascade. Subsequent phosphorylation of GSK3β and β-catenin by PKA facilitates the stabilization and nuclear translocation of β-catenin. RESULTS: L-DOPA supplementation significantly enhances the efficiency of RPE induction, as well as the maturity and functionality of iRPE. Moreover, L-DOPA-treated iRPE cells demonstrated robust resistance to oxidative stress and exhibited improved therapeutic effects in RCS rats after transplantation, alleviating retinal degeneration and preserving retinal function. CONCLUSION: These findings highlight the potential of L-DOPA as a promising adjunct for iRPE differentiation and stem cell-based therapies for RDDs.
Exosome-derived LncRNAs in bone remodeling: recent advances and future directions for bone disease therapy.
Zhang S, Wang H, Zhao C … +8 more , Zhu C, Li X, Su Z, Zou J, Wang C, Zhang L, Yuan Y, Tian X
Stem Cell Res Ther · 2026 Jun · PMID 42231470 · Full text
BACKGROUND: Exosomes derived from various cellular sources play a pivotal role in mediating and regulating bone and cartilage regeneration for conditions such as bone defects, fractures, cartilage repair, osteoporosis, a...
BACKGROUND: Exosomes derived from various cellular sources play a pivotal role in mediating and regulating bone and cartilage regeneration for conditions such as bone defects, fractures, cartilage repair, osteoporosis, and osteoarthritis. MAINTEXT: As essential intercellular communication vehicles, exosomes transmit long non-coding RNAs (lncRNAs) to modulate cellular behaviors in the bone microenvironment, which has been a central focus of contemporary research.This review consolidates existing evidence on exosome-derived lncRNAs in bone remodeling, revealing their regulatory roles through signaling pathway networks on osteoclasts, osteoblasts, and related bone/cartilage lineage cells, including mesenchymal stem cells, chondrocytes, and osteoclasts. Exosome-encapsulated lncRNAs that regulate osteogenic differentiation of bone marrow mesenchymal stem cells, osteoclast activity, bone-vascular coupling, and bone metastasis show promise as minimally invasive biomarkers for diagnosis, risk stratification, and therapeutic monitoring of bone metabolic disorders. CONCLUSION: Moreover, harnessing exosomes as natural, engineerable delivery vehicles can advance the development of bone-targeted, precise, and low-toxicity therapeutic strategies to complement existing pharmacologic and regenerative treatments.
Development of a novel GAK solution for efficient hypothermic preservation of NK cell viability and anti-tumor function.
Wang X, Liu X, Wu G … +10 more , Wang H, Yu K, Liu Y, Xu H, Sun X, An Z, Zhao L, Shi C, Huang M, Wang Z
Stem Cell Res Ther · 2026 Jun · PMID 42226278 · Full text
BACKGROUND: Natural killer cells exhibit significant potential within current immunotherapeutic modalities. Hypothermic preservation is a critical step for the clinical transportation and temporary storage of NK cell pro...
BACKGROUND: Natural killer cells exhibit significant potential within current immunotherapeutic modalities. Hypothermic preservation is a critical step for the clinical transportation and temporary storage of NK cell products. However, during this process, both cell viability and function significantly decrease. The core damage mechanisms remain unclear, and effective, specialized preservation protocols are currently lacking. This study aimed to elucidate the primary modes of cell death and maintain NK cell potency during hypothermic preservation. METHODS: This study first evaluated the effects of different intravenous fluids and temperatures on NK cell preservation efficiency. Subsequently, various cell death inhibitors, molecular biomarker assays, and electron microscopy techniques were utilized to systematically elucidate the modes of cell death. Based on these findings, we optimized the best-performing fluids by replacing sodium lactate with glucose to enhance energy supply, adding the antioxidant α-tocopherol to mitigate oxidative stress, and elevating the potassium ion concentration (to 22.5 mM) to suppress excessive nutrient uptake and associated oxidative damage. These optimizations were incorporated into a new formulation designated as the GAK solution. The preservation efficacy was comprehensively assessed through in vitro cell viability and cytotoxicity assays, as well as an in vivo leukemia xenograft model. RESULTS: Storage at 4 °C was much better than at 25 °C. Among the tested intravenous fluids, lactated Ringer's demonstrated the highest efficacy in preserving NK cell viability and function. NK cells undergo complex death pathways during hypothermic preservation, specifically ferroptosis, pyroptosis, and necroptosis. Our optimized GAK effectively mitigates energy depletion and oxidative stress, significantly maintaining the viability and potent cytotoxic capacity of NK cells against various tumor cells after hypothermic storage. In vivo experiments further demonstrated that NK cells preserved in the GAK solution maintained significant antitumor activity, which contributed to prolonged survival in tumor-bearing mice. CONCLUSIONS: This study revealed multiple death mechanisms of NK cells during hypothermia and successfully developed a well-defined and highly efficient GAK solution. The GAK solution presents a new approach to the hypothermic preservation of NK cells, facilitating the efficient and convenient transport of NK cell products, which has significant practical implications for the accelerated clinical adoption of cellular immunotherapy.
Construction of liver organoid models by hepatobiliary differentiation from human induced pluripotent stem cells: state of the art, challenges and improving strategies.
Wu YH, Wang Y, Zhang WJ … +2 more , Yuan LL, Chen Y
Stem Cell Res Ther · 2026 Jun · PMID 42226068 · Full text
Physiologically relevant liver models are essential for advancing hepatic disorder research, especially for disease modeling and drug development, yet current in vitro systems fail to adequately recapitulate the architec...
Physiologically relevant liver models are essential for advancing hepatic disorder research, especially for disease modeling and drug development, yet current in vitro systems fail to adequately recapitulate the architecture and function of the liver. Owing to the accessibility, robust proliferation and multilineage differentiation potential of human induced pluripotent stem cells (iPSCs), liver organoids derived from iPSCs have emerged as a promising resource in hepatology. Despite this promise, the field still faces persistent bottlenecks including incomplete hepatic maturation, insufficient incorporation of non-parenchymal cells (notably immune and stromal populations), phenotypic instability, and a lack of consensus on standardized differentiation protocols. Therefore, this review systematically analyzes the challenges and strategies of iPSC differentiation into liver organoids and the related influencing factors by focusing on multidimensional regulation of hepatobiliary development as well as the effects of cellular origin, culture system and liver microenvironment on hepatic differentiation of iPSCs. Moving forward, priority should be given to the following directions: (1) Elucidating the self-assembly mechanism of liver organoids to enable precise control of hepatobiliary differentiation, thereby better governing organoid morphology and improving reproducibility; (2) Replacing exogenous cytokines with small-molecule compounds at different stages of iPSC differentiation to simplify and standardize differentiation protocols; (3) Advancing liver organoid transplantation as a means to validate physiological functionality and shift cell therapy from passive replacement toward active tissue reconstruction; (4) Integrating artificial intelligence to achieve intelligent and precise regulation of hepatic differentiation.
SPHERpower: MSC spheroid-based bioequivalent lead to the efficient restoration of the scarred vocal folds.
Shpichka A, Svistushkin M, Khristidis Y … +14 more , Bikmulina P, Serejnikova N, Fayzullin A, Lebedeva G, Bakulina A, Zolotova A, Zinchenko I, Kosheleva N, Fayzullina N, Belovolov M, Efremov Y, Solovieva A, Svistushkin V, Timashev P
Stem Cell Res Ther · 2026 May · PMID 42218554 · Full text
Cell-based therapy has become an attractive option to restore the vocal folds (VF) after scarring. Despite that first clinical trials using mesenchymal stromal cells (MSC) suspension has been launched, there is still an...
Cell-based therapy has become an attractive option to restore the vocal folds (VF) after scarring. Despite that first clinical trials using mesenchymal stromal cells (MSC) suspension has been launched, there is still an issue of retaining cells at implantation site to prolong their effects. Therefore, cell spheroids are considered to be a part of next generation bioequivalents. This study aims to reveal the safety and efficacy of MSC spheroid-based bioequivalent in treating VF scars in comparison with cell suspension. To evaluate this approach in vivo, a rabbit vocal fold scar model was established in 48 male rabbits, which were allocated to four groups: untreated control, PEG-fibrin, PEG-fibrin with MSC suspension, and PEG-fibrin with MSC spheroids. In 3 months post operation, in group where the MSC suspension-based bioequivalent was implanted, the mature connective tissue was located beneath the epithelium without dystrophic changes and had a relatively loose ECM; the thickness of the lamia propria was higher than that in the intact VF. In group where we used the MSC spheroid-based bioequivalent the loose connective tissue consisted of longitudinally oriented collagen fibers, spindle-shaped fibroblasts; the lamia propria was relatively thin (116.42 ± 42.77 μm) and loose and did not differ from the intact VF. Both types enabled the VF restoration; nevertheless, the use of MSC spheroids lead to more efficient regeneration: the tissue architectonics and mechanical properties of the treated VF was more similar to those of the intact VF.
Mechanical stretch loading of BMSCs-PLCL composite scaffolds accelerate diabetic wound healing by protecting endothelial cells and promoting angiogenesis.
Liu Z, Zhao C, Zhou H … +8 more , Shi Z, Huang R, Xu L, Su J, Chen G, Zhao Z, Li Y, Li J
Stem Cell Res Ther · 2026 May · PMID 42218551 · Full text
BACKGROUND: Impaired angiogenesis is a critical factor that delays diabetic wound healing. Although bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential, their paracrine functions are suppressed in hyper...
BACKGROUND: Impaired angiogenesis is a critical factor that delays diabetic wound healing. Although bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential, their paracrine functions are suppressed in hyperglycemic environments. This study aimed to construct a stem cell-scaffold construct by integrating BMSCs with poly(L-lactic-co-ε-caprolactone) (PLCL) nanofiber scaffolds and applying cyclic mechanical stretch to enhance the function of BMSCs, thereby promoting angiogenesis and tissue repair in diabetic wounds. METHODS: The efficacy of mechanically stretched BMSCs-PLCL (MS-BMSCs-PLCL) composite scaffolds was evaluated in a full-thickness skin defect model using diabetic rats. Immunofluorescence staining was used to assess the expression of CD31, α-SMA and vascular endothelial growth factor (VEGF) to evaluate angiogenesis and vascular maturation. The in vivo fate of PKH26-labeled BMSCs was tracked post-transplantation. Additionally, CCK-8 assay, EdU staining, scratch assay, Transwell assay, and tube formation assay analyzed the effects of mechanical stretch-preconditioned BMSCs and their conditioned medium (CM) on high-glucose-injured rat umbilical vein endothelial cells (RUVECs). RNA-seq was performed to elucidate the mechanism underlying the pro-angiogenic enhancement of BMSCs under mechanical stretch, followed by functional validation via knockdown of the identified Postn gene. RESULTS: The MS-BMSCs-PLCL composite scaffolds significantly enhanced the healing process of diabetic wounds. Immunofluorescence staining showed that MS-BMSCs-PLCL upregulated CD31, α-SMA, and VEGF expression, promoting angiogenesis and vascular maturation. Cell tracing confirmed the transplanted BMSCs were co-localized with the endothelial marker CD31. In vitro, both mechanically stretched BMSCs and their CM improved the proliferation, migration, and tube formation of high glucose-injured RUVECs. RNA-seq analysis identified key genes involved in angiogenesis and tissue repair that were altered by mechanical stimulation. Functional analysis confirmed that silencing Postn attenuated the pro-angiogenic function of mechanically stretched BMSCs. CONCLUSION: Mechanical stretch enhanced the paracrine function of BMSCs, thereby promoting angiogenesis in diabetic wounds and reversing endothelial cells damage from high glucose. These findings support a novel strategy that combines mechanical preconditioning, biomaterials, and stem cells for improving diabetic wound healing.
Mesenchymal stem cells and extracellular vesicles for MAFLD: from biological mechanisms to translational prospects.
Huang Z, Pan Y, Liao N … +1 more , Pan F
Stem Cell Res Ther · 2026 May · PMID 42216085 · Full text
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent metabolic disorder that can progress from simple steatosis to chronic inflammation and fibrosis. Currently, pharmacological agents for MAFLD rem...
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent metabolic disorder that can progress from simple steatosis to chronic inflammation and fibrosis. Currently, pharmacological agents for MAFLD remain limited, and lifestyle-based management often fails to halt disease progression, underscoring the need for multitarget therapeutic strategies. Mesenchymal stem cells (MSCs) represent a promising regenerative and immunomodulatory therapy capable of reprogramming the hepatic inflammatory microenvironment, improving metabolic homeostasis, and limiting fibrogenesis. Increasing evidence indicates that MSC efficacy is largely mediated through paracrine mechanisms, with MSC-derived small extracellular vesicles (MSC-EVs) acting as key effectors by delivering functional cargos, including microRNAs (miRNAs) and proteins. MSC-EVs attenuate inflammation via inflammasome inhibition and macrophage polarization, restore insulin sensitivity and lipid handling through AMP-activated protein kinase (AMPK)-associated metabolic signaling, and also limit fibrogenesis by suppressing hepatic stellate cell (HSC) activation as part of their integrated multitarget actions. This review integrates current insights into MAFLD pathogenesis and the therapeutic mechanisms of MSCs and MSC-EVs, and highlights translational priorities for their clinical development.
Exosomes in bone health and disease: cellular crosstalk, systemic signaling, and AI-driven advances in regenerative therapy.
Liu X, Yu W, Huang C … +4 more , Wang Z, Qian Y, Chen X, Chen G
Stem Cell Res Ther · 2026 May · PMID 42216068 · Full text
Exosomes have emerged as critical mediators of intercellular and inter-organ communication in bone biology. Secreted by bone-resident cells such as osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells (MSCs),...
Exosomes have emerged as critical mediators of intercellular and inter-organ communication in bone biology. Secreted by bone-resident cells such as osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells (MSCs), these nanosized vesicles carry diverse molecular cargos that regulate bone remodeling, regeneration, and skeletal homeostasis. In addition to mediating local communication within the bone microenvironment, exosomes also participate in systemic crosstalk communication between bone and other tissues, including skeletal muscle, adipose tissue, gut microbiota, the immune system, the nervous system, and vasculature. Disruption of these exosome-mediated pathways contributes to the development and progression of bone diseases, including osteoporosis, osteoarthritis, osteonecrosis of the femoral head, and bone metastases. This review summarizes current advances in exosome-mediated signaling in both physiological and pathological contexts, with particular emphasis on their roles as biomarkers, therapeutic agents, and drug delivery vehicles. We also discuss the emerging contribution of artificial intelligence (AI) to exosome research, especially in biomarker discovery, disease classification, and target identification, as well as the major challenges that currently limit clinical translation. Together, these insights highlight the potential of exosome-based strategies for precision medicine in bone diseases.
KRT6A derived from mesenchymal stem cells as a potential biomarker and therapeutic target for alopecia areata: insights from multi-omics analysis and experimental evidence.
Peng S, Deng J, Meng X … +3 more , Deng S, Yan W, Huang X
Stem Cell Res Ther · 2026 May · PMID 42216026 · Full text
BACKGROUND: Mesenchymal stem cells (MSCs) secretome have shown promise in the treatment of alopecia areata (AA). However, the key therapeutic genes remain unclear. This study aimed to identify potential critical therapeu...
BACKGROUND: Mesenchymal stem cells (MSCs) secretome have shown promise in the treatment of alopecia areata (AA). However, the key therapeutic genes remain unclear. This study aimed to identify potential critical therapeutic molecules using multi-omics approaches. METHODS: MSCs extracellular vesicles related genes was retrieved from ExoCarta database, and which integrated with transcriptomic and proteomic sequencing data from AA for cross-analysis to identify AA-related therapeutic genes. Mfuzz clustering, PPI networks, and machine learning algorithms were employed to potential key therapeutic factors. Functional mechanisms were explored through gene expression analysis, immune infiltration, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. AA mice were used for experimental validation. RESULTS: We identified 146 MSCs-derived genes with potential therapeutic relevance for AA. Enrichment analysis suggests that they are involved in skin development and differentiation. Through Mfuzz clustering, 13 machine learning algorithms, and combined with SHAP interpretability analysis, the KRT6A was we further identified as the most critical candidate gene. Validation analyses demonstrated that KRT6A serves as a robust diagnostic marker for AA (AUC = 0.989), a predictor of disease severity (AUC = 0.769), and a protective factor (HR = 0.52, 95%CI: 0.34-0.79). Immune infiltration analysis revealed severe immune dysregulation in AA, and KRT6A was significantly negative correlated with dysregulated immune cells. By exploring the expression source of KRT6A, we found that it was mainly enriched in skin hair follicle tissues, and single-cell subset analysis and spatial transcriptomics further mapped KRT6A to hair follicle stem-like cells from the cellular level, yet KRT6A was significantly downregulated in AA models. Primary human hair follicle mesenchymal stem cells (HFMSCs) further confirmed KRT6A localization. Furthermore, KRT6A-overexpressing HFMSCs exhibited enhanced migration, whereas KRT6A knockdown reduced migration and suppressed WNT pathway activation. Conditioned medium from KRT6A-overexpressing HFMSCs effectively alleviated alopecia and reduced apoptosis in AA mice, whereas KRT6A knockdown reversed these effects. CONCLUSION: MSCs-derived KRT6A may serve as a potentia biomarker and therapeutic target for AA, which provide novel insights into AA pathogenesis and may help the development of targeted therapeutic strategies.
Human adipose-derived mesenchymal stromal cells in vitro expansion for regenerative applications: tracking small genetic variants reveals dynamic changes within a genetically stable framework.
Neri S, Bartolotti I, Pedrini E … +3 more , Manferdini C, Assirelli E, Ursini F
Stem Cell Res Ther · 2026 May · PMID 42204587 · Full text
BACKGROUND: The extended use of mesenchymal stromal cells (MSC) for cellular therapies raises safety concerns, and preliminary controls are needed before clinical application to guarantee patient safety. In vitro expansi...
BACKGROUND: The extended use of mesenchymal stromal cells (MSC) for cellular therapies raises safety concerns, and preliminary controls are needed before clinical application to guarantee patient safety. In vitro expansion is frequently required to obtain sufficient material, with an increased risk of appearance and selection of genetically altered or senescent cells, which could impair not only safety but also the biological potential and therapeutic efficacy of these cells. In vitro manipulated MSCs must adhere to the guidelines of Good Manufacturing Practices including the verification of genomic stability, transformation potential and senescence. Several tests are currently used, mainly karyotyping, which enables the detection of large alterations. Small alterations, albeit potentially important, are usually not evaluated, except for selected known mutations in a few crucial genes. METHODS: Here, the potential of Next Generation Sequencing (NGS) to detect small DNA alterations was exploited as a reliable tool to monitor the genetic stability of cells manipulated prior to therapeutic application. The acquisition of small somatic mutations during in vitro culture of human adipose-derived mesenchymal stromal cells from 23 osteoarthritis patients was investigated at different times from passage 1 to passage 10 using targeted NGS of a panel of human cancer-related genes. Moreover, copy number variations in selected genes were analyzed using both the 'Coverage Analysis' plugin and digital PCR. RESULTS: Overall genetic stability was maintained, despite the emergence of sporadic variants, some with pathogenic potential or of uncertain significance, reflecting dynamic changes in culture. No copy number variations occurred during in vitro culture. CONCLUSIONS: Time in culture is confirmed as a key variable influencing the acquisition of genetic alterations, underscoring the importance of minimizing expansion times to preserve genetic stability. Given the potential impact of small genetic alterations on cellular function and the high next generation sequencing processivity and throughput, exploring incoming mutations in MSC cells via NGS turns out to be not only a perspective research pursuit, but also a robust strategy for surveillance of genetic stability. Integrating this approach into quality control guidelines would support standardized monitoring of the genomic integrity of manipulated MSCs prior to clinical application.
Construction of pre-vascularized bone-like tissue by incorporation of mesodermal progenitor cells through simulating endochondral ossification.
Guan Y, Wang Z, Wang H … +6 more , Huang R, Lin J, Wang Y, Ma D, Zhou P, Ren L
Stem Cell Res Ther · 2026 May · PMID 42178573 · Full text
BACKGROUND: Pre-vascularized cartilage enhances bone regeneration (intrachondral osteogenesis) and accelerates bone defect healing. While current strategies focus on co-culturing chondrocytes with endothelial cells, matu...
BACKGROUND: Pre-vascularized cartilage enhances bone regeneration (intrachondral osteogenesis) and accelerates bone defect healing. While current strategies focus on co-culturing chondrocytes with endothelial cells, mature endothelial cells inhibit the necessary osteogenic transformation. To overcome this, we implemented a co-differentiation strategy using human induced pluripotent stem cells (hiPSCs)-derived mesodermal progenitor cells (iMPCs) instead. We generated pre-vascularized cartilage aggregates by 3D co-culture of these iMPCs with hiPSC-derived chondrocytes (Chos) and evaluated their osteogenic potential. This approach offers new insights and potential strategies for repairing bone defects. METHODS: HiPSCs were differentiated into iMPCs (characterized by FLK1(VEGF-R) expression, CD31/vWF immunofluorescence, tube formation, flow cytometry) and Chos (confirmed by SOX9/COL2/ACAN qRT-PCR, Alcian blue staining, VEGF165 ELISA). Pre-vascularized aggregates were generated by 3D co-culture of iMPCs and Chos in ultra-low attachment plates (monocultures as controls). After 14 days, aggregates were assessed in vitro for vascularization (CD31 immunofluorescence), gene/protein expression (qRT-PCR/immunofluorescence for IHH, ALP, COL1A1), and mineralization (Alizarin Red). In vivo osteogenesis was evaluated by implanting aggregates into rat calvarial defects, analyzing healing at 4/8 weeks via Micro-CT, histology (H&E, Masson's trichrome), and neovascularization (CD31 immunohistochemistry). RESULTS: IMPCs exhibited high endothelial potential, with a 52.84% induction rate and the ability to form tube-like structures. Co-culture aggregates developed extensive CD31⁺ vascular networks in vitro. Pre-vascularization significantly promoted chondrocyte hypertrophy (increased IHH expression), early osteogenesis (elevated ALP activity and COL1A1 expression), and enhanced in vitro mineralization compared to controls (*p < 0.05). In vivo, the pre-vascularized group demonstrated improved bone defect repair, as shown by increased bone volume in micro-CT analysis, histological evaluation (H&E and Masson's trichrome), enhanced host-derived vascular integration (CD31⁺ staining), and advanced bone maturation relative to control groups (*p < 0.05). CONCLUSION: Our findings indicate that this vascularization approach utilizing mesodermal cells successfully achieves pre-vascularization of cartilage aggregates in vitro, while also facilitating cartilage hypertrophy and early osteogenic transformation. In vivo study revealed that pre-vascularized cartilage aggregates exhibited more nascent vasculature and enhanced bone formation compared to cartilage aggregates alone.
Organoids: generation strategies, applications, and future challenges.
Yin H, Zhu GQ, Wang HZ … +3 more , Yang BB, Wang ZX, Xie H
Stem Cell Res Ther · 2026 May · PMID 42174698 · Full text
Organoids are microscopic 3D structures that resemble real organs, assembled in vitro from stem cells. Since the Dutch team of Hans Clevers successfully cultured intestinal stem cells to generate intestinal structures in...
Organoids are microscopic 3D structures that resemble real organs, assembled in vitro from stem cells. Since the Dutch team of Hans Clevers successfully cultured intestinal stem cells to generate intestinal structures in 2009, organoid technology has developed rapidly, and culture protocols covering various organs such as the brain, liver, intestine, kidney, and bone have been established. These micro-organ models retain the cellular heterogeneity, tissue-specific structure, and genetic background of the original tissue. Compared to traditional two-dimensional culture, they provide a more physiologically relevant research platform. This article reviews organoid generation strategies, mainly dividing them into scaffold-free and scaffolded methods, and details specific generation protocols for brain, liver, intestine, kidney, and bone organoids. Furthermore, this article emphasizes innovations in bioengineering, such as organ-on-a-chip systems and 3D bioprinting technology. These technologies can enhance the maturity, vascularization, and reproducibility of organoids. The article also extensively discusses the biomedical applications of organoids, including in vitro disease models, infectious diseases, cancer, drug screening and toxicity testing, tissue engineering, and age-related diseases. Despite the significant potential of organoids, some challenges remain. Issues such as standardization, limited vascularization, ethical considerations, and scalability for industrial and clinical translation remain. Looking ahead, interdisciplinary efforts integrating stem cell biology, bioengineering, and computational methods promise to drive the development of organoid technology. This will make it a more robust and physiologically consistent model. Organoids hold the potential to become a cornerstone tool in biomedical research, bridging the gap between in vitro research and the clinical application of personalized medicine, drug development, and regenerative therapies.
HA-UCMSCs as an innovative therapy for treating multiple organ dysfunction syndrome.
Hu JX, Li Y, Gao M … +9 more , Li ZA, Zhao XJ, Chen MD, Ye L, Li Q, Ye QQ, Wang Q, He J, Pan X
Stem Cell Res Ther · 2026 May · PMID 42169186 · Full text
BACKGROUND: Multiple organ dysfunction syndrome (MODS) is highly lethal and lacks effective therapies. Umbilical cord-derived mesenchymal stem cells (UCMSCs) regulate immunity, suppress inflammation, and promote tissue r...
BACKGROUND: Multiple organ dysfunction syndrome (MODS) is highly lethal and lacks effective therapies. Umbilical cord-derived mesenchymal stem cells (UCMSCs) regulate immunity, suppress inflammation, and promote tissue repair, suggesting potential benefit for MODS. However, despite over 1400 MSC-related clinical studies worldwide, inconsistent outcomes reflect the lack of potent, standardized products. Our group established highly active UCMSCs (HA-UCMSCs) with enhanced proliferative and reparative capacity. This study evaluated their efficacy in MODS and explored underlying mechanisms. METHODS: MODS was induced in tree shrews by combining hemorrhagic shock, simulated infection, and hind limb compression. HA-UCMSCs were isolated, expanded, and characterized for their nuclear-to-cytoplasmic ratio, proliferation rate, multilineage differentiation capacity, and expression of mesenchymal and embryonic stem cell surface markers. After intravenous infusion, therapeutic efficacy was assessed via hematological and biochemical parameters, histopathological analysis, and serum proteomics using data-independent acquisition (DIA) mass spectrometry. RESULTS: HA-UCMSCs exhibited enhanced biological features compared to conventional UCMSCs, including high proliferative capacity and ESC marker expression. In vivo, HA-UCMSCs homed to injured organs, alleviated systemic inflammation, facilitated tissue regeneration, and maintained hematopoietic homeostasis. Treatment significantly reduced mortality and long-term disability in MODS. DIA proteomic analysis identified 18 candidate serum proteins associated with disease progression and treatment efficacy. CONCLUSION: This study introduces a clinically relevant tree shrew model of MODS and demonstrates the multi-organ protective effects of HA-UCMSCs. These findings highlight HA-UCMSCs as a promising stem cell-based therapy for MODS and propose novel serum biomarkers for treatment monitoring.
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