Stem Cell Res Ther [JOURNAL]
Sun
200 papers
Pretreatment of metanephric mesenchymal cells with catalpol mitigates acute kidney injury through VEGF-A secretion via multiple mechanisms.
Ji P, Xie Y, Guo W … +5 more , Jiang Q, Bi J, Han B, Yin Z, Fu B
Stem Cell Res Ther · 2026 Mar · PMID 41904548 · Full text
BACKGROUND: Metanephric mesenchymal cells (MMCs) hold therapeutic potential for acute kidney injury (AKI), but their efficacy is limited, and the mechanisms underlying their action remain unclear. This study aimed to inv...
BACKGROUND: Metanephric mesenchymal cells (MMCs) hold therapeutic potential for acute kidney injury (AKI), but their efficacy is limited, and the mechanisms underlying their action remain unclear. This study aimed to investigate whether catalpol-pretreated MMCs (MMCs-cata) could enhance the efficacy of AKI treatment by regulating key signaling pathways. METHODS: An AKI model was established in C57BL6 mice via intraperitoneal injection of cisplatin, and the therapeutic effects of MMCs-cata were compared with those of untreated MMCs. RNA-Seq was performed to analyze differentially expressed genes, Western blotting and ELISA were used to measure VEGF-A levels in MMC-cata and the supernatants. An in vitro model of cisplatin-induced renal tubular epithelial cell injury was developed to investigate the signaling pathways upstream and downstream of VEGF-A. The role of VEGF-A/VEGFR2 was confirmed through experiments involving gene silencing, neutralizing antibodies, and VEGFR2 blockade. Additionally, molecular docking simulations and Western blotting were performed to explore the effects of catalpol on the Wnt signaling pathway. RESULTS: MMCs-cata significantly improved renal function in AKI model mice by suppressing inflammation, oxidative stress, and necroptosis. RNA-Seq, Western blotting and ELISA revealed the activation of VEGF-related genes in MMCs-cata along with elevated intracellular and supernatant VEGF-A levels. In both the in vivo and in vitro models, silencing VEGF-A in MMCs-cata, neutralizing VEGF-A in the supernatant, or blocking VEGFR2 in tubular epithelial cells abolished the protective effects of MMCs-cata, while exogenous VEGF-A supplementation alone exerted protective effects. Mechanistic studies indicated that MMCs-cata activated the p38 pathway and suppressed the STAT3 pathway. Molecular docking and Western blotting confirmed that catalpol binds to Wnt3A, activating the canonical Wnt pathway to drive VEGF-A secretion. CONCLUSION: Catalpol pretreatment enhances the therapeutic efficacy of MMCs by activating the canonical Wnt pathway to promote VEGF-A secretion. VEGF-A interacts with VEGFR2 on renal tubular epithelial cells, likely through both p38 pathway activation and STAT3 pathway inhibition, thereby suppressing inflammation, oxidative stress, and necroptosis to alleviate AKI. This study provides novel insights into the integration of traditional Chinese medicine components with stem cell therapy for AKI management.
Research based on serine metabolism indicates mesenchymal stem cells alleviate psoriasis by regulating the PSPH-PINK1-Parkin-NLRP3 pathway in HaCaT.
Lin Q, Ji Y, Yang B … +3 more , Zhu R, Song P, Zhao RC
Stem Cell Res Ther · 2026 Mar · PMID 41904508 · Full text
BACKGROUND: Psoriasis is a refractory immune-related disease. In recent years, it has been discovered that mesenchymal stem cells (MSCs) can be used as a new therapeutic approach for psoriasis, but their potential therap...
BACKGROUND: Psoriasis is a refractory immune-related disease. In recent years, it has been discovered that mesenchymal stem cells (MSCs) can be used as a new therapeutic approach for psoriasis, but their potential therapeutic mechanism remains unclear. This study aims to explore the role of MSCs in the treatment of psoriasis. METHODS: We employed a mouse psoriasis model induced by imiquimod (IMQ) in vivo and a co-culture system of MSCs and HaCaT keratinocytes (KCs) cell line in vitro. These approaches allowed us to investigate the effect of MSCs on the levels of inflammatory factors and the activation of inflammasomes in both contexts. Mouse-targeted amino acid sequencing, transmission electron microscopy for in vitro observation, immunofluorescence for both in vivo and in vitro analyses, and siRNA transfection in vitro were employed in this study. RESULTS: Our results showed that MSCs significantly improved the skin lesion of mice with psoriasis, and reduced the levels of inflammatory factors and chemokines including IL-1β, IL-6, IL-8, TNF-α, MCP-1, CCL7, CCL20 and CCL27 in the mouse skin lesion areas and M5- induced psoriatic KCs models in vitro. Likewise, MSCs repaired the skin barrier by enhancing claudin-1 expression in vivo. In addition, MSCs increased KRT1 and decreased KRT6 levels in vivo and in vitro. Amino acid metabolism analysis showed that MSCs could improve the serine metabolism level in the mouse skins and upregulated the key enzyme phosphoserine phosphatase (PSPH) in serine metabolism. In vitro experiments demonstrated that knockdown of PSPH could reverse the therapeutic effects of MSCs on psoriasis. Furthermore, studies in vitro and in vivo revealed that MSCs can activate the PINK1-Parkin pathway. It was specifically manifested by elevated levels of PINK1, Parkin, p-Parkin, Beclin-1, and LC3B-II/I, coupled with a reduction in P62 protein. Subsequently, the activation of PINK1-Parkin led to decreased expressions of IL-1β, IL-6, IL-8, TNF-α, CCL7, CCL20, CCL27, and MCP-1. In vitro and in vivo experiments indicated that MSCs can reduce the levels of IL-1β, IL-6, IL-8, TNF-α, CCL7, CCL20, CCL27, and MCP-1 by inhibiting the activation of NLRP3 inflammasomes. Meanwhile, PSPH knockdown in vitro can reverse the activating effects of MSCs on the PINK1-Parkin, as shown by decreased levels of PINK, Parkin, p-Parkin, Beclin-1, and LC3B-II/I, concurrently with an elevation in P62.. CONCLUSIONS: The results of this study indicated that MSCs can alleviate IMQ-induced psoriasiform dermatitis in mice by upregulating serine metabolism. The key serine metabolism enzyme PSPH may enhance PINK1/Parkin-mediated mitochondrial autophagy in psoriatic HaCaT and inhibit NLRP3 inflammasome activation in HaCaT cells, thereby alleviating skin inflammatory responses and suppressing skin p roliferation in psoriatic mice.
Preclinical efficacy of combination therapy with allogeneic induced pluripotent stem cell-derived invariant natural killer T and α-galactosylceramide-pulsed antigen-presenting cells.
Aoki T, Kobayashi M, Okoshi M … +14 more , Yamaguchi M, Okura H, Sasaki S, Sasako Y, Kira S, Chang YH, Yakushiji-Kaminatsui N, Sharif J, Matsuda M, Kiuchi M, Hirahara K, Kimura MY, Motohashi S, Koseki H
Stem Cell Res Ther · 2026 Mar · PMID 41904478 · Full text
Invariant natural killer T (iNKT) cells, upon activation, exhibit antitumor roles by bridging innate and acquired immunity. To overcome the challenges in producing iNKT cells from patients with cancer, we previously deve...
Invariant natural killer T (iNKT) cells, upon activation, exhibit antitumor roles by bridging innate and acquired immunity. To overcome the challenges in producing iNKT cells from patients with cancer, we previously developed allogeneic human induced pluripotent stem cell-derived iNKT (iPSC-iNKT) cells. However, the activation of iPSC-iNKT cells by glycolipid ligands remains a critical step for iNKT cell-mediated cancer therapy. To show the effect of iPSC-iNKT cell-mediated antitumor immunity, in this preclinical study, by taking advantage of a human immune cell-transplanted patient-derived xenograft model using human IL-7/15 knock-in NSG mice, we demonstrate that a combination of iPSC-iNKT cells and α-galactosylceramide-pulsed antigen-presenting cells (αGalCer/APC) induces robust antitumor effects. Single-cell analysis of tumor-infiltrating lymphocytes revealed that this combination therapy uniquely expanded tumor-reactive memory-phenotype CD4 and CD8 T cells. Taken together, upon activation by αGalCer/APC, iPSC-iNKT cells are capable of effectively inducing antitumor T cell immunity, making them a promising tool for generating personalized antitumor T cell immunity.
Phenotypic alterations and PI3K-AKT pathway regulation in senescence of human tonsil mesenchymal stem cells.
Qiu X, Lin Z, Sun Y … +2 more , Zhao A, Chen X
Stem Cell Res Ther · 2026 Mar · PMID 41896931 · Full text
BACKGROUND: Tonsil mesenchymal stem cells (TMSCs) are a promising regenerative medicine source but require continuous subculturing for expansion. Long-term expansion in vitro induces cellular senescence, impairing their...
BACKGROUND: Tonsil mesenchymal stem cells (TMSCs) are a promising regenerative medicine source but require continuous subculturing for expansion. Long-term expansion in vitro induces cellular senescence, impairing their function. This study aimed to elucidate senescence-related phenotypic alterations and regulatory mechanisms in human tonsil-derived mesenchymal stem cells. METHODS: Human-derived TMSCs were isolated from palatine tonsils, cultured under standard conditions, and characterized for mesenchymal markers. Senescence-associated changes were evaluated across early (P1-P5) and late passages (beyond P10). Proliferation capacity was assessed via CCK-8 assays, while senescence-associated β-galactosidase (SA-β-gal) activity and protein levels of p16, p53, and p21 were quantified. RNA sequencing identified differentially expressed genes (DEGs) between young and senescent TMSCs, followed by KEGG pathway enrichment analysis. Key findings were validated by measuring the p-Akt/Akt ratio via Western blot. RESULTS: TMSCs showed a progressive decline in proliferative capacity with increasing passages. SA-β-gal staining revealed a significantly higher percentage of positive cells in late-passage TMSCs compared to early-passage cells. Expression levels of P16, P53, and P21 proteins were markedly upregulated in aged TMSCs. KEGG analysis of DEGs indicated significant enrichment in the PI3K-Akt signaling pathway, ECM-receptor interaction, and calcium signaling. Consistent with this, Western blot confirmed a significantly increased p-Akt/Akt ratio in senescent TMSCs. CONCLUSION: Our research proved that replicative senescence in TMSCs is associated with PI3K-Akt pathway activation, which likely orchestrates senescence via p16 and p53-p21 cascades. These findings provide new insights into the mechanisms of stem cell aging and suggest potential molecular targets for developing strategies to delay senescence in TMSCs for regenerative medicine.
Proliferation-dependent adipogenic differentiation of progenitor cells in rat coronary artery explants.
Kazantzi S, Reducha PV, Haanes KA
Stem Cell Res Ther · 2026 Mar · PMID 41896918 · Full text
BACKGROUND: Lipid accumulation is involved in pathogenesis of cardiovascular disease. Progenitor cells are associated with the disease progression; however, their identity remains unclear. We therefore set out to investi...
BACKGROUND: Lipid accumulation is involved in pathogenesis of cardiovascular disease. Progenitor cells are associated with the disease progression; however, their identity remains unclear. We therefore set out to investigate whether adipogenic differentiation occurs in rat coronary artery explants, identify progenitor cells involved, and determine the role of proliferation in this process. METHODS: Rat coronary artery explants were cultured ex vivo in adipogenic differentiation medium for 14 days. Lipid accumulation and adipocyte marker secretion were assessed using Oil Red O staining, LipidSpot immunofluorescence, and ELISA for FABP4 and adiponectin. Progenitor cell identity and proliferation were characterized by immunofluorescence for Gli1, Ki67, vimentin, and BrdU incorporation at specific intervals. Pharmacological inhibition of proliferation occurred using BrdU and confirmed with the MEK1/2 inhibitor trametinib. Transcriptomic profiling compared adipocyte-enriched and progenitor-enriched populations. RESULTS: Coronary artery segments cultured under adipogenic conditions accumulated lipids and secreted FABP4 and adiponectin over time. Gli1 progenitor cells initially localized in the arterial wall and subsequently migrated outward, forming lipid-laden adipocyte-like cells. Continuous inhibition of proliferation occurred with BrdU and with trametinib, both of which significantly reduced lipid accumulation and adiponectin secretion, demonstrating the necessity of early proliferative activity. Transcriptomic analysis of the cells confirmed distinct populations of white adipocyte-like cells expressing lipid metabolic genes and a progenitor population with a biosynthetic and translational profile. CONCLUSIONS: This study provides the first evidence in rat coronary artery explants of proliferation-dependent adipogenic differentiation from Gli1 progenitors. Early proliferative events are crucial for initiating adipogenesis, highlighting mechanisms potentially relevant to coronary vascular remodelling in disease.
Epidural cell therapy reduces neurological sequelae severity in canine distemper survivors.
Cardoso do Prado Bayma J, Baracho Trindade Hill JE, Molina AB … +1 more , Baracho Trindade Hill A
Stem Cell Res Ther · 2026 Mar · PMID 41882793 · Full text
BACKGROUND: Canine distemper has a high mortality rate in the acute phase, and survivors typically suffer irreversible, progressive neurological sequelae, due to demyelinating leukoencephalitis, under current treatment s...
BACKGROUND: Canine distemper has a high mortality rate in the acute phase, and survivors typically suffer irreversible, progressive neurological sequelae, due to demyelinating leukoencephalitis, under current treatment standards. Mesenchymal stromal cells (MSCs) are found in the adult organism and represent a promising alternative for treating central nervous system disorders by secreting trophic and immunomodulatory factors that reduce inflammation, protect neurons, and promote regeneration. The therapeutic action of MSCs is largely mediated by the secretion of trophic and immunomodulatory factors, including anti-inflammatory cytokines, anti-apoptotic proteins, and neurotrophins. METHODS: The objective of this study was to evaluate the effects of three epidurally administered doses of 1 million MSCs per kilogram of body weight at 30-day intervals in four dogs suffering neurological sequelae of canine distemper. Each animal was evaluated using an adapted application of the modified neurodisability scale (0-15 scale) and a quality-of-life questionnaire ranking behaviors (0-7 scale). RESULTS: Statistical analysis confirmed the significant effect of using multiple doses, and regression analysis revealed a significant influence of age and weight on treatment outcome. Additionally, a logistic regression predicting improvement over time was extrapolated from these results to help clinicians and owners make better-informed decisions regarding cellular therapy. Complete clinical remission of four of the five subcategories of the neurodisability score was achieved in all subjects, with one subject achieving full remission of myoclonus. CONCLUSIONS: These results indicate that epidural MSC administration progressively reduced sequelae severity and improved patient quality of life of the four canine distemper survivors that participated in this study, supporting the translation of cellular therapies into clinical practice.
Comprehensive assessment of the genomic stability of human induced pluripotent stem cells for clinical applications.
Zhang K, Na T, Jia C … +9 more , Yuan X, Guo M, Yang X, Li M, Jia W, Bai Z, Lu J, Liu Z, Meng S
Stem Cell Res Ther · 2026 Mar · PMID 41877289 · Full text
BACKGROUND: Human induced pluripotent stem cells (hiPSCs) may acquire genomic alterations during reprogramming and culture, which poses significant risks for clinical applications. Current detection methods, such as kary...
BACKGROUND: Human induced pluripotent stem cells (hiPSCs) may acquire genomic alterations during reprogramming and culture, which poses significant risks for clinical applications. Current detection methods, such as karyotyping analysis, often fail to identify critical submicroscopic variations. This highlights an urgent need for comprehensive genomic surveillance strategies. METHODS: Three human iPSC lines were continually cultured in vitro for 50 passages, with genome alterations evaluated every 10 passages. The evaluation methods included karyotyping to detect chromosomal abnormalities, optical genome mapping (OGM) to identify copy number variations (CNVs) and structural variants (SVs), whole-exome sequencing (WES) to detect coding mutations, and RNA sequencing (RNA-seq) to detect the changes of gene expression. RESULTS: We detected accumulating chromosomal abnormalities (e.g., trisomy 12), SVs, CNVs, and sequence mutations in three hiPSC lines during extended culture. OGM effectively identified SVs and CNVs below karyotyping resolution, particularly recurrent genome abnormalities such as gains on chr17q, chr12p and chr20q. WES revealed coding mutations, including germline short variants and newly acquired somatic mutations, some of which were associated with tumors or diseases, such as CDH1, BCOR. Transcriptional changes correlated with genomic alterations, including dysregulation of oncogenes such as BCL2L1, KRAS and MDM2. Results demonstrate that each method had unique detection capabilities and limitations, and only integrative approaches can comprehensively identify genomic abnormalities. CONCLUSIONS: This study established a comprehensive strategy for evaluating the genomic alterations of hiPSCs by integrating karyotyping, OGM, WES, and RNA-seq. This comprehensive strategy can be applied to scenarios such as hiPSC clone screening, establishment of cell bank passages, and quality control of hiPSC-derived products. It provides a reliable genetic stability evaluation protocol to support the safe clinical application of hiPSC-related products.
IFN-γ induces hematopoietic stem cell myelopoiesis through Meis1 in tumor.
Han X, Zhao M, Wang K … +8 more , Ma W, Zhu S, Zhou R, Yu U, Jiang B, Bai X, Lei P, Wang S
Stem Cell Res Ther · 2026 Mar · PMID 41877254 · Full text
BACKGROUND: The role of inflammation-induced myeloid-biased hematopoiesis in driving resistance to immune checkpoint blockade (ICB) is recognized, yet the intricate mechanisms through which tumors orchestrate it are not...
BACKGROUND: The role of inflammation-induced myeloid-biased hematopoiesis in driving resistance to immune checkpoint blockade (ICB) is recognized, yet the intricate mechanisms through which tumors orchestrate it are not fully defined. METHODS: MC38 tumor and Lewis lung cancer models were performed to evaluate hematopoietic stem cells (HSCs) differentiation biased. Key pro-inflammatory cytokines implicated in this process were screened through ELISA assay and bioinformatic analysis. Subsequent mechanistic investigations identified the central transcription factor governing tumor-induced myeloid-biased differentiation of HSCs. To demonstrate the functional impact on antitumor immunity, we quantified HSC-derived myeloid-derived suppressor cells (MDSCs) and assessed their suppressive effects on T cell function. Furthermore, the therapeutic potential of targeting this axis was evaluated using Emapalumab, an anti-IFN-γ antibody, to determine whether suppressing myeloid-biased HSCs could enhance the antitumor effects of ICB. RESULTS: Here, we found HSCs exhibit a persistent myeloid-biased differentiation phenotype in MC38 tumor and Lewis lung cancer models, which was induced by the pro-inflammatory cytokines IFN-γ. Transcriptional profiling indicated Meis homeobox 1 (Meis1) was enriched in tumor primed HSCs, and ablation of Meis1 in HSCs prevented HSCs-associated myeloid cell differentiation. The resulting HSC-derived MDSCs were identified as key factors of tumor progression. Therapeutic targeting of the myeloid differentiation axis with a combination of anti-PD-1 antibody and Emapalumab, an anti-IFN-γ antibody inhibited HSC-derived MDSCs production and enhanced T cells-mediated adaptive immunity to suppress tumor progression. CONCLUSIONS: Our results highlight HSC-directed therapy as a novel approach for cancer treatment. Combining anti-PD-1 with Emapalumab potently enhances the response to ICB, offering a promising strategy to achieve superior and durable anticancer efficacy.
Mesenchymal stromal cells as add-on therapy to anti-CD25 antibodies for treating gastrointestinal-involved steroid-refractory acute graft-versus-host disease: a multicenter, single-arm, pivotal clinical trial.
Zheng Y, Wang L, Mo X … +7 more , Zhang Y, Li Y, Han M, Yang D, Zhang X, Liu D, Jiang E
Stem Cell Res Ther · 2026 Mar · PMID 41877188 · Full text
BACKGROUND: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is the predominant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with gastrointestinal in...
BACKGROUND: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is the predominant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), with gastrointestinal involvement (SR-GI-aGVHD) remaining a key obstacle. We conducted a multicenter, single-arm, pivotal trial to assess the efficacy and safety of hUC-MSC PLEB001, a human umbilical cord-derived mesenchymal stromal cells (MSCs) product, plus anti-CD25 monoclonal antibody as second-line therapy for SR-GI-aGVHD. METHODS: Eligible patients with grade II or higher SR-GI-aGVHD received hUC-MSC PLEB001 with protocol-defined anti-CD25 monoclonal antibody therapy. hUC-MSC PLEB001 was infused at a dose of 10 cell/kg twice weekly for 4 consecutive weeks, starting at day 1, and efficacy was assessed on day 28. Patients achieving complete response (CR), progressive disease (PD) or no response (NR) concluded treatment; those with partial response (PR) continued the same regimen for additional 4 weeks. The primary endpoint of the study is the overall response rate (ORR) at day 28. RESULTS: Fifty-four patients (median age 43, range 14-68) were enrolled. The number of Grade II-IV SR-aGVHD patients was 21, 16, 17, respectively. Thirty-seven patients were GI-involved only, 15 patients were GI and skin involved, and 2 patients were GI and liver involved. The ORR at day 28 was 63.0% (95% CI 48.7%, 75.7%), with a CR rate of 55.6% (41.4%, 69.1%). The 28-day durable complete response rate (DCR) was 51.9% (37.8%, 65.7%). The ORR and CR rate at day 56 was 51.9% (37.8%, 65.7%) and 50.0% (36.1%, 63.9%), respectively. The overall survival (OS) for full analysis set (FAS) at day 28, 56, 100, 360 for the entire cohort were 94.4% (83.8%, 98.2%), 88.9% (76.9%, 94.9%), 79.6% (66.2%, 88.2%), 65.8% (51.1%, 77.0%) respectively. Treatment was well tolerated, and no infusion-related toxicity or treatment-related serious adverse events were observed. CONCLUSIONS: In this multicenter single-arm study, hUC-MSC PLEB001 plus anti-CD25 monoclonal antibody therapy was associated with clinically meaningful response rates and an acceptable safety profile in patients with SR-GI-aGVHD. These findings support further evaluation of MSC-based approaches within multimodal treatment algorithms for this challenging condition. TRIAL REGISTRATION: Registry: Chinese Clinical Trial Registry, TRN: ChiCTR2300073965, Registration date: 2023-07-26 (retrospectively registered).
Donor age and sex program MSC secretome signaling: a quadrant framework for precision therapy.
Azad T, Hong K, Wu F … +8 more , Mao J, Zhou X, Xie H, Qiu X, Li B, Zhang L, Tian J, Wen C
Stem Cell Res Ther · 2026 Mar · PMID 41877175 · Full text
BACKGROUND: Clinical responses to mesenchymal stromal cell (MSC) therapies remain variable because MSCs are often treated as uniform biologics despite donor-programmed differences. Evidence indicates that developmental m...
BACKGROUND: Clinical responses to mesenchymal stromal cell (MSC) therapies remain variable because MSCs are often treated as uniform biologics despite donor-programmed differences. Evidence indicates that developmental maturity (fetal vs. adult) and biological sex (female vs. male) bias the MSC secretome and downstream signalling (NF-κB, PI3K/AKT-ERK, TGF-β/Smad, Wnt/β-catenin), potentially shaping anti-inflammatory, angiogenic, anti-fibrotic, and regenerative functions. METHODS: We conducted a targeted synthesis of peer-reviewed in vitro, preclinical, and early clinical studies that relate donor features (maturity, sex) to secretome mediators (EV miRNAs/proteins; cytokines/growth factors) and pathway readouts. Findings were organized along mediator→pathway→function chains and distilled into a rule-based quadrant model (fetal♀, fetal♂, adult♀, adult♂), with qualitative consideration of tissue source and manufacturing variables. RESULTS: Consistent donor-programmed skews emerged: fetal female MSCs enrich IL-10/TSG-6 and miR-125a with NF-κB suppression and Treg/DC-tolerizing activity; fetal male MSCs elevate VEGF/bFGF/HGF with PI3K/AKT-ERK activation supporting angiogenic survival; adult female MSCs show TGF-β/Smad tuning compatible with anti-fibrotic remodelling; adult male MSCs upregulate WNT5A/IGF-1/Runx2, favouring regenerative/osteogenic programmes with comparatively lower oxidative-stress resilience. We translate these patterns into fit-for-purpose potency/CQA panels (e.g., IL-10/TSG-6; VEGF/HGF with pAKT/pERK; TGF-β/Smad; WNT5A/IGF-1/Runx2) and concise trial schemas (stratification by maturity×sex; pathway-anchored pharmacodynamic biomarkers). CONCLUSIONS: A signaling-centered, donor-stratified framework may help organize heterogeneous findings in the MSC field and generate testable predictions for potency assessment, indication matching, and study design. Because most available evidence evaluates sex or maturity in isolation and under diverse tissue sources and manufacturing conditions, the proposed quadrant model should be interpreted as hypothesis-generating. Prospective, harmonized, head-to-head validation across donor quadrants will be required to determine its translational utility.
From bench to bedside: advances in cell therapy for tuberculosis treatment.
Chunxiao L, Junsheng F, Xuerong C … +2 more , Xiaomin W, Shuihua L
Stem Cell Res Ther · 2026 Mar · PMID 41866557 · Full text
Tuberculosis (TB) remains a major global public health challenge, with drug-resistant tuberculosis (DR-TB) presenting a serious threat to TB management. Conventional treatment faces challenges such as significant drug to...
Tuberculosis (TB) remains a major global public health challenge, with drug-resistant tuberculosis (DR-TB) presenting a serious threat to TB management. Conventional treatment faces challenges such as significant drug toxicity, frequent emergence of drug resistance, and compromised host immune microenvironment. These limitations, particularly in DR-TB cases, often lead to poor treatment outcomes and heightened recurrence rates, underscoring the need for complementary strategies. Cell-based host-directed therapy (HDT) emerges as a novel therapeutic strategy that may complement conventional drugs by directly modulating pathological immune responses and facilitating the repair of damaged tissue. This narrative review synthesizes preclinical and clinical data on cell therapy for TB. We focus on two distinct strategic approaches: (1) mesenchymal stem cell (MSC)-based therapies, which primarily exert immunomodulatory and tissue-repair functions, and (2) T cell-based adoptive cell therapies (ACTs), which are designed to enhance antimicrobial immunity directly. Current evidence, while promising, predominantly remains in the early exploratory stages or lacks robust evidence-based support. To facilitate successful translation, future research should focus on standardizing cell products, conducting comprehensive safety assessments and implementing more rigorous clinical trials. This review critically assesses the therapeutic potential and translational challenges of cell therapy for TB.
A review of the circadian regulation of stem cells: harnessing the internal body clock for enhanced regenerative therapies.
Alnasser SM
Stem Cell Res Ther · 2026 Mar · PMID 41866513 · Full text
BACKGROUND: Circadian rhythms are endogenous, transcription-translation feedback loops that align cellular activities with the 24-h light-dark cycle. Stem-cell populations across tissues exhibit circadian oscillations th...
BACKGROUND: Circadian rhythms are endogenous, transcription-translation feedback loops that align cellular activities with the 24-h light-dark cycle. Stem-cell populations across tissues exhibit circadian oscillations that influence their self-renewal, proliferation, and differentiation. Key developmental pathways (Wnt/β-catenin, Notch, and Hedgehog) are increasingly recognized as both regulators and targets of circadian machinery. OBJECTIVES: This review synthesizes current knowledge on the bidirectional crosstalk between circadian clock components and major stem-cell regulatory pathways, and evaluates how this interplay shapes tissue homeostasis, regenerative capacity, and therapeutic potential. METHODS: Literature examining molecular interfaces between circadian clock genes and Wnt, Notch, and Hedgehog signaling was surveyed, with emphasis on transcriptional regulation, chromatin dynamics, post-translational control, and functional outcomes for stem-cell behavior and regeneration. RESULTS: Evidence indicates that core clock components modulate stem-cell pathways through direct transcriptional control, shared enhancer architecture, altered chromatin accessibility, and rhythmic protein modification. In turn, Wnt, Notch, and Hedgehog signals feed back onto clock genes, influencing circadian amplitude and phase within stem-cell niches. Perturbation of this reciprocal regulation disrupts tissue maintenance, diminishes regenerative responses, alters metabolic equilibrium, and may promote tumorigenesis. CONCLUSIONS: Circadian oscillators act as temporal gatekeepers of stem-cell function. Mapping the molecular interfaces between clock genes and developmental signaling pathways reveals new opportunities to refine regenerative therapies. Chronotherapeutic strategies, i.e. timing interventions to intrinsic circadian phases may enhance the efficacy, precision, and safety of stem-cell-based treatments.
Preclinical efficacy and safety evaluation of human embryonic stem cell-derived functional hepatocytes for a clinical trial in acute liver failure.
Sun Y, Yu J, Shi Y … +10 more , Wang Y, Duan X, Xie M, Ouyang Q, Zhao Y, Wang M, Zhou B, Xu C, Lu G, Lin G
Stem Cell Res Ther · 2026 Mar · PMID 41866506 · Full text
BACKGROUND: Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid deterioration of liver function, resulting in high mortality and posing a substantial global health burden. Human embryonic stem...
BACKGROUND: Acute liver failure (ALF) is a life-threatening syndrome characterized by rapid deterioration of liver function, resulting in high mortality and posing a substantial global health burden. Human embryonic stem cells (hESCs) possess unlimited self-renewal capacity and pluripotent differentiation potential. Transplantation of hESC-derived hepatocyte-like cells (HPLCs) represents a promising therapeutic strategy for ALF. METHODS: A good manufacturing practice (GMP)-compliant differentiation process was developed to generate HPLCs from hESCs, and their biological characteristics and functional properties were systematically evaluated. A comprehensive series of preclinical safety and efficacy studies was performed, including dose-escalation experiments, biodistribution analysis, comparative evaluation of administration routes, and carcinogenicity testing. The therapeutic efficacy and safety of HPLCs were assessed in a fatal rat model of D-galactosamine (D-gal) and lipopolysaccharide (LPS)-induced ALF. In addition, the HPLCs underwent quality evaluation by the National Institutes for Food and Drug Control (NIFDC), and an independent safety assessment was conducted. RESULTS: A high-efficiency system was established for the generation of qualified, clinical-grade HPLCs from hESCs under GMP-compliant conditions. The HPLCs exhibited multiple mature hepatocyte functions, including carbohydrate and lipid metabolism, hepatic synthetic and storage functions, inducible cytochrome P450 activity, albumin secretion, and urea production. The HPLCs met the certification standards of the NIFDC of China. Transplantation of HPLCs significantly improved survival in ALF rats, with survival rates of 72.4% following tail vein injection and 66.7% following intraperitoneal injection, compared with 6.67% in the control group. HPLC transplantation also promoted recovery of liver function, as reflected by improvements in biochemical and coagulation parameters. Preclinical safety evaluations confirmed the biosafety of HPLCs, with no evidence of acute toxicity or tumorigenicity. A Phase I clinical trial (ChiCTR2100052988) for the treatment of ALF and acute-on-chronic liver failure (ACLF) has been approved by the National Health Commission of the People's Republic of China (Filing Number: MR-43-21-014643) and has been initiated. CONCLUSIONS: A novel multistage, GMP-compliant process was developed for the effective and reproducible differentiation of hESCs into hepatocytes. The resulting HPLCs demonstrated robust hepatocyte functions, therapeutic efficacy in an ALF animal model, and favorable biosafety profiles. These findings support the clinical translation of HPLCs, with an ongoing Phase I clinical trial designed to evaluate their safety and feasibility in patients with ALF and ACLF.
Advances in retinal pigment epithelium transplantation for age-related macular degeneration: bridging biology to therapeutic frontiers.
Bhargava M, Mehta KN, Parikh BH … +2 more , Liu Z, Su X
Stem Cell Res Ther · 2026 Mar · PMID 41866494 · Full text
Stem cell-derived RPE replacement is a potential therapeutic for advanced AMD that is characterized by macular scarring and geographic atrophy leading to severe vision loss. Although the field of stem cell-differentiated...
Stem cell-derived RPE replacement is a potential therapeutic for advanced AMD that is characterized by macular scarring and geographic atrophy leading to severe vision loss. Although the field of stem cell-differentiated RPE transplantation has undergone significant evolution, important gaps in our knowledge remains unaddressed. Long-term RPE cell survival and integration into the neural retina post-transplantation has yet to be established. Employing advanced imaging techniques and transcriptomics to study cellular integration and immune tolerance post-transplant, will improve our understanding. In addition, a better understanding of RPE bioenergetics, in the context of cell therapy, is crucial for developing more effective therapeutics. This is especially important for stem cell therapy, typically derived from varying somatic cells of origin, with inherently distinct metabolic profiles. This review focuses on current approaches to improve the outcomes of RPE transplantation, and thereby facilitate robust development of retinal cell therapy, to address the unmet clinical needs of patients with advanced AMD.
HC-HA/PTX3 from amniotic membrane reprograms human corneal fibroblasts to neural crest progenitors by switching from canonical to noncanonical TGFβ signaling.
Zhu YT, Tighe S, Zhang Y … +2 more , Helman A, Tseng SCG
Stem Cell Res Ther · 2026 Mar · PMID 41865000 · Full text
BACKGROUND: HC-HA/PTX3 (a complex formed by high molecular weight hyaluronan covalently linked to heavy chain 1 of inter-α-trypsin inhibitor and tightly bound to pentraxin 3) is a unique extracellular matrix from human a...
BACKGROUND: HC-HA/PTX3 (a complex formed by high molecular weight hyaluronan covalently linked to heavy chain 1 of inter-α-trypsin inhibitor and tightly bound to pentraxin 3) is a unique extracellular matrix from human amniotic membrane that exerts an anti-scarring action and reprograms human corneal fibroblasts (HCF) and myofibroblasts to corneal stromal keratocytes in the absence of transforming growth factor β1 (TGFβ1) by downregulating canonical Smad-mediated signaling and upregulating bone morphogenetic protein (BMP) signaling. It remains unclear whether HC-HA/PTX3 can further reprogram HCF into neural crest (NC) progenitors in the presence of TGFβ1. METHODS: Human corneal fibroblasts were seeded on plastic, immobilized hyaluronic acid (HA) or HC-HA/PTX3 or on plastic with or without soluble HA and HC-HA/PTX3 in DMEM + 10% fetal bovine serum (FBS), with or without various inhibitors with or without TGFβ1. Transcript expression of NC and signaling markers was determined by RT-qPCR. Immunostaining was performed to monitor cytolocalization of signaling markers and α-smooth muscle actin (α-SMA). Raft separation before Western blot was used to study protein distributions in both rafts. Western blot and ELISA were used to measure relative protein level. RESULTS: Herein, we show for the first time that in the presence of exogenous TGFβ1, HC-HA/PTX3 continues to reprogram HCF into NC progenitors by upregulating mRNA expression of NC markers, confirmed by successful induction into human corneal endothelial cells, highlighted by hexagonal shape, mRNA expression of corneal endothelial markers and junctional staining of corneal endothelial markers such as Na-K-ATPase, α-catenin, β-catenin, F-actin, N-cadherin, p120 and ZO-1 but the lack of fibrogenic marker S100A4. Such reprogramming requires suppression of TGFβ1 SMAD-mediated canonical signaling that starts from HC-HA/PTX3 binding with CD44 to sequester type II TGFβ receptor (TβRII) in lipid raft and ends with downregulation of TβRII by nuclear translocation of cyclin D1. Mechanistically, nuclear translocation of cyclin D1 is mediated by activation of transforming growth factor-beta-activated kinase 1-transcription factor Jun (TAK1-cJUN) noncanonical signaling because of type I TGFβ receptor (TβRI) and type III TGFβ receptor (TβRIII) (without TβRII) in non-lipid raft as well as by nuclear translocation of CD44 intracellular domain (CD44ICD) formed by Membrane Type 1 Matrix Metalloproteinase (MT1MMP)/γ-secretase cleavage to facilitate such reprogramming. CONCLUSIONS: Thus, HC-HA/PTX3 from amniotic membrane can be deployed as a new strategy to reverse scar toward regeneration.
Targeting p75NTR activity alleviates the neurotoxic effect of high glucose on iPSC-derived dopaminergic neurons.
Chanoumidou K, Zota I, Papadopoulou MA … +9 more , Konstantinou C, Tsimpolis A, Tsagliotis E, Tziortziou M, Ntarntani K, Grünewald A, Lavigne MD, Gravanis A, Charalampopoulos I
Stem Cell Res Ther · 2026 Mar · PMID 41864949 · Full text
BACKGROUND: Hyperglycemia, a hallmark of diabetes mellitus, is a metabolic condition that highly affects the nervous system. While evidence from epidemiological and animal studies links diabetes to dopaminergic dysfuncti...
BACKGROUND: Hyperglycemia, a hallmark of diabetes mellitus, is a metabolic condition that highly affects the nervous system. While evidence from epidemiological and animal studies links diabetes to dopaminergic dysfunction and an increased risk of Parkinson's disease, the underlying mechanisms remain unclear. Here, we examined the effects of high glucose on human iPSC-derived dopaminergic neurons and glial cells to better understand the pathogenic alterations that lead to neurotoxicity. Previous implication of neurotrophins in the neurological manifestations of diabetes prompted us to focus on the role of p75NTR neurotrophin receptor (p75NTR) in dopaminergic neurodegeneration under hyperglycemic conditions. METHODS: iPSC-derived dopaminergic neurons, astrocytes and microglia were treated with high glucose (50mM, 100mM) for 48 h to simulate hyperglycemia. Cytotoxicity assays, RNA sequencing and DNA damage assessments were employed to investigate the pathological alterations induced by high glucose exposure in neurons. Pharmacological targeting of p75NTR activity allowed investigation of its involvement in glucose neurotoxicity. Glial-mediated neurotoxicity was evaluated using conditioned media and inflammatory marker analysis. RESULTS: High glucose treatment led to DNA damage, activation of JNK signaling and cell death in neurons. Importantly, we observed upregulation of p75NTR and its pro-apoptotic ligand pro-NGF, suggesting activation of the pro-NGF/p75NTR axis in high glucose-treated neurons. Inhibition of p75NTR activity rescued neuronal cell death, identifying p75NTR as a central mediator of glucose neurotoxicity. Furthermore, glucose overload sensitized neurons to 6-hydroxydopamine (6-OHDA), increasing their vulnerability to neurotoxic insults-an effect reversed by p75NTR blockade. Treatment with BNN27, a synthetic NGF mimetic, prevented neuronal loss through p75NTR and TrkA receptors, suggesting neurotrophin signaling as a potential therapeutic target for combating high glucose-induced neuronal damage. Finally, we demonstrated the contribution of glial cells to neurodegeneration since high glucose treatment of iPSC-derived astrocytes and microglia enhanced their inflammatory potential and triggered the release of neurotoxic factors, causing pro-apoptotic effects on neurons. CONCLUSIONS: Our findings show that high glucose impairs human dopaminergic neuron survival through activation of the pro-NGF/p75NTR axis and indirect glia-mediated mechanisms. Targeting p75NTR signaling may offer neuroprotective benefits in diabetes-related neurodegeneration, particularly for patients at risk of Parkinson's disease.
DS96432529 enhances osteogenic differentiation and mitigates inflammatory damage in periodontal ligament stem cells involving mitophagy-related processes.
He H, Huang J, Yuan J … +11 more , Chen Y, Zhou Y, Cheng B, Shi L, Chen X, Yang D, Zhao M, Li D, Zeng X, Hu T, Liu Z
Stem Cell Res Ther · 2026 Mar · PMID 41863006 · Full text
AIM: Periodontitis can impair the osteogenic function of periodontal ligament stem cells (PDLSCs), thereby compromising their capacity for periodontal tissue regeneration. In this study, we explored the impact of a synth...
AIM: Periodontitis can impair the osteogenic function of periodontal ligament stem cells (PDLSCs), thereby compromising their capacity for periodontal tissue regeneration. In this study, we explored the impact of a synthetic small molecule, DS96432529 (DS), on the osteogenic differentiation potential of PDLSCs and its underlying mechanism. METHODS: The viability of DS was assessed by cell proliferation assays and apoptosis analysis. Osteogenic potential was evaluated through alkaline phosphatase (ALP) activity staining and Alizarin Red S (ARS) staining for mineralized nodule formation. Inflammatory injury was induced using recombinant tumor necrosis factor-alpha (TNF-α). RNA sequencing analyzed signaling pathways involved in DS-enhanced osteogenic differentiation. Western blotting quantified key pathway protein expression. Specific small molecule inhibitors and agonists modulated relevant signaling pathways. Therapeutic efficacy was evaluated in a ligature-induced rat periodontitis model. RESULTS: DS inhibited cell proliferation at lower concentrations but did not induce significant apoptosis at concentrations up to 250 nM. Across tested concentrations, DS significantly enhanced ALP activity and accelerated mineralized nodule formation in PDLSCs. DS upregulated mitophagy-related protein expression under both inflammatory and non-inflammatory conditions. Additionally, DS restored TNF-α-inhibited ALP activity and attenuated TNF-α-induced activation of the RIG-I-like receptor (RLR) signaling pathway. The RIG-I activator Poly(I: C) counteracted DS-mediated repair of inflammatory injury during osteogenesis. Mitophagy inhibition diminished DS's beneficial effects on osteogenic differentiation under inflammation and reduced its suppression of RIG-I expression. DS alleviated ligation-induced alveolar bone loss in rats with periodontitis. CONCLUSIONS: DS enhances the osteogenic potential of PDLSCs in association with the activation of mitophagy-related processes. It mitigates inflammation-impaired osteogenesis, potentially via modulation of the RIG-I-mediated RLR signaling pathway, in association with increased mitophagy-related activity. DS represents a potent therapeutic small molecule for ameliorating periodontitis-induced bone loss.
Rejuvenation of mesenchymal stromal cells via partial reprogramming enables scalable generation of transcriptionally diverse MSC libraries.
Tu H, Hosaka A, Hichiwa G … +13 more , Wang Y, Kazuki K, Tabata T, Osaki M, Nakayama Y, Kanazawa I, Honma K, Kimura MT, Gao X, Ogata N, Abe S, Oshimura M, Kazuki Y
Stem Cell Res Ther · 2026 Mar · PMID 41862988 · Full text
BACKGROUND: Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but their clinical utility is limited by replicative senescence. Strategies that reverse aging while maintaining MSC identity are urg...
BACKGROUND: Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but their clinical utility is limited by replicative senescence. Strategies that reverse aging while maintaining MSC identity are urgently needed. METHODS: We developed a non-integrating, temperature-sensitive Sendai virus (SeV)-mediated rejuvenation protocol transiently expressing hTERT, BMI1, and SV40T in human MSCs. Following SeV removal, we evaluated proliferation, telomere length, karyotype stability, transcriptomic reset, producing heterogeneity, and differentiation potential. RESULTS: Rejuvenated MSCs (rej-MSCs) demonstrated extended proliferation beyond 100 days, telomere elongation, and normal karyotypes after SeV clearance. Transcriptomic profiling showed a reset of senescence-associated programs while retaining mesenchymal identity. Functional analyses revealed clone-specific heterogeneity, including HGF-driven angiogenic activity. Multilineage differentiation capacity was preserved across rej-MSCs. CONCLUSIONS: This transient, non-integrating rejuvenation strategy establishes an operational definition of rej-MSCs and provides a transcriptionally diverse and scalable platform for MSC manufacturing and precision therapy design.
Hydrogel-based delivery of MSCs and derivatives for improved diabetic retinopathy therapy.
Sun L, Qi Y, Zhang Y … +5 more , Zhang Z, Fan Z, An C, Zhao L, Zhang L
Stem Cell Res Ther · 2026 Mar · PMID 41862936 · Full text
Diabetic retinopathy (DR), the most prevalent ocular complication of diabetes, progresses from non-proliferative (NPDR) to sight-threatening proliferative (PDR) stages. Current interventions-including retinal photocoagul...
Diabetic retinopathy (DR), the most prevalent ocular complication of diabetes, progresses from non-proliferative (NPDR) to sight-threatening proliferative (PDR) stages. Current interventions-including retinal photocoagulation, intravitreal anti-VEGF agents, and surgery-address advanced disease, often require repeated administration, and carry risks like retinal injury. Safer, more effective, and longer-lasting treatments are needed, especially for early-stage DR. Mesenchymal stem cells (MSCs) and their derivatives offer a promising alternative, with advantages including low immunogenicity, paracrine signaling, and the ability to mitigate inflammation and vascular permeability. However, challenges in delivery efficiency and targeting specificity remain. Hydrogel-based scaffold materials are increasingly important due to their superior biocompatibility and ability to overcome ocular barriers. Recent advances include novel injectable hydrogels that can be combined with drugs or stem cells, enabling targeted delivery to retinal layers, prolonging therapeutic retention, and significantly improving bioavailability for sustained treatment of DR.
Progress in human intestinal organoid research: applications to acute gastroenteritis viruses.
Zhang K, Li H, Zhou Y
Stem Cell Res Ther · 2026 Mar · PMID 41851900 · Full text
Acute gastroenteritis viruses, such as rotavirus, human norovirus, human astrovirus, human adenovirus, human sapovirus, represent significant threats to global public health. Research on these pathogens has long been ham...
Acute gastroenteritis viruses, such as rotavirus, human norovirus, human astrovirus, human adenovirus, human sapovirus, represent significant threats to global public health. Research on these pathogens has long been hampered by the limitations of conventional models. Animal and cell-based systems, widely used in virological studies, show limited efficiency in supporting rotavirus replication, while noroviruses remain largely non-cultivable in these settings. Organoids-complex, three-dimensional multicellular structures derived from stem cells-exhibit organ-specific characteristics and spatial organization, making them promising tools for viral research. Intestinal organoids, in particular, recapitulate key features of the gut epithelium and have emerged as versatile platforms for investigating viral pathogenesis and developing intervention strategies. This review systematically outlines the cultivation and functional properties of human intestinal organoids, as well as the evolution and progress of their application in studying acute gastroenteritis viruses. However, current intestinal organoid models are primarily composed of epithelial cells and lack immune and other non-epithelial components, thereby limiting their ability to fully simulate host-pathogen interactions and immune responses following infection. Future efforts should focus on incorporating emerging technologies, such as CRISPR/Cas9 gene editing, to develop more physiologically relevant intestinal models that better mimic in vivo conditions.
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