Stem Cells Translational Medicine最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) is reversible at early stages, making early identification critical. We previously demonstrated that patient-derived induced pluripotent stem cells (iPSCs) carrying MASLD-associated genetic risk variants exhibit greater oleate-induced intracellular lipid accumulation than those without these variants. This study aimed to develop an iPSC-based MASLD risk predictor using functional lipid accumulation assessments. We quantified oleate-induced lipid accumulation in iPSCs from three cohorts: (1) CIRM (22 cases, 20 controls), (2) POST (18 cases, 16 controls), and (3) UCSF (4 cases, 8 controls). Data from the CIRM cohort was used to define an iPSC-based MASLD risk score, which was subsequently validated in the POST and UCSF cohorts. Lipid accumulation was consistently higher in MASLD iPSCs across cohorts. The risk score achieved 44% sensitivity/75% specificity in POST and 75%/100% in UCSF. These findings suggest that oleate-induced lipid accumulation in iPSCs may be a predictor of MASLD risk. Larger studies incorporating additional cellular phenotypes, clinical, and genetic data could enhance predictive accuracy for MASLD surveillance and prevention.

Spinal cord injury (SCI) causes irreversible neurological damage and remains a major clinical challenge due to the lack of effective regenerative therapies. Human-induced pluripotent stem cells (hiPSCs) and their derivatives, hiPSC-derived neural stem/progenitor cells (hiPSC-NS/PCs), have demonstrated potential to promote neural repair and functional recovery. The world's first clinical trial using hiPSC-NS/PCs in the subacute phase of SCI has already been initiated. In contrast, chronic SCI-despite accounting for the majority of clinical cases-remains difficult to treat due to pathological barriers such as widespread demyelination, cavitation, scar formation, and persistent inflammation. Recent efforts to overcome these obstacles include combinatorial strategies incorporating rehabilitation, biomaterial scaffolds, pharmacological adjuvants, and robotic-assisted therapy as well as gliogenic or regionally patterned hiPSC-NS/PCs. Preclinical models have demonstrated that such multifaceted approaches can enhance graft survival, axonal regeneration, and functional recovery. In this review, we provide an overview of the biological characteristics, mechanisms of action, and recent advances in preclinical and clinical research on hiPSC-NS/PCs transplantation for SCI. We also discuss future perspectives and challenges toward clinical application. Collectively, these efforts underscore the diverse, innovative, and translational potential of hiPSC-based regenerative medicine for SCI.

Background: Cerebral palsy (CP), primarily caused by perinatal cerebral hypoxia and ischemia, is a devastating neurological disease in children characterized by motor, behavioral, and cognitive disorders. This study aimed to evaluate the therapeutic effects of amniotic membrane mesenchymal stem cell-derived exosome-rich conditioned medium (ERCM) in a CP model.

Methods: ERCM components were analyzed using enzyme-linked immunosorbent assay. Biodistribution was examined via fluorescence-labeled ERCM in both normal and CP induced animals. In vitro, the neuroprotective effects of ERCM against lipopolysaccharide and potassium cyanide-induced cytotoxicity were assessed in human neural stem cells and oligodendrocyte progenitor cells, focusing on apoptosis, inflammation, and oligodendrocyte differentiation. In vivo, ERCM was injected into CP-induced animals, followed by evaluation of antiapoptotic and anti-inflammatory signaling, motor and cognitive function, and white matter integrity.

Results: ERCM contained a broad array of growth factors and demonstrated enhanced retention in CP-affected brain regions. In vitro, ERCM significantly reduced apoptos is and inflammation, and promoted oligodendrocyte maturation via upregulation of Nkx2.2, CN Pase, and MBP. In vivo, ERCM treatment improved motor and cognitive performance, in hibited cell death and inflammatory responses, and increased expression of oligodendrocyte markers, including Nkx2.2, Olig2, CNPase, and MBP via increasing growth factor expression. Furthermore, ERCM attenuated demyelination in the corpus callosum, a region particularly vulnerable in CP.

Conclusion: ERCM confers therapeutic benefits in CP by preserving neural stem and oligodendrocyte progenitor cells, modulating apoptosis and inflammation, and enhancing oligodendrocyte differentiation. Accordingly, ERCM may present a good candidate as a CP therapeutic agent.

Whole-body exposure to ionizing radiation can lead to cellular DNA damage to bone marrow (BM), causing lethal hematopoietic acute radiation syndrome (H-ARS). Extracellular vesicles (EVs) from human BM-derived mesenchymal stromal cells were primed with CRX-527 (CRX), a synthetic TLR4 agonist, characterized and tested as a radiomitigator therapy. Using a xenogeneic H-ARS mouse model, a single in vivo treatment with CRX-EVs administered 4 or 24 hours after lethal irradiation significantly improved weight loss, clinical scores and prolonged survival compared to control treatments. Ex vivo generation of CRX-EV educated monocytes (CRX-EEMos) were also effective in a H-ARS model when administered 24 hours after lethal irradiation. CRX-EVs or CRX-EEMos significantly promoted hematopoiesis in BM and potentially the spleen, leading to restoration of peripheral complete blood counts. CRX-EEMos showed increased gene expression of IL-6 and IL-10: enriched for PD-L1 but low for CD16 in CD14-expressing monocytes. Antisense inhibition of Let-7 microRNAs in CRX-EEMos suppressed IL-10 gene expression and protein secretion, implicating a novel role for Let-7 in radioprotection. CRX-EVs can effectively treat H-ARS by increasing the secretion of anti-inflammatory molecules while stimulating monocytes to promote hematopoiesis in BM. The potential for large-scale production of CRX-EVs as an "off-the-shelf" treatment for H-ARS makes them a potential medical countermeasure for radiological and nuclear threats.

Vascular remodeling, a precursor to atherosclerosis and coronary heart disease, is associated with high morbidity and mortality in individuals with diabetes. The roles of endothelial-mesenchymal transition (EndMT) and human umbilical cord mesenchymal stem cells (hUCMSCs) in this process remain unclear. In this study, we used db/db mice as a diabetic model to investigate the effect of hUCMSCs on metabolic reprogramming and vascular remodeling. We analyzed serum markers, tissue morphology, metabolomics, and endothelial cell-specific proteomics. The results demonstrated that vascular remodeling and EndMT were exacerbated in diabetes and alleviated by hUCMSCs. Metabolomic analysis identified 209 altered metabolites. Most metabolic intermediates were increased, while anti-inflammatory metabolites such as arachidonoyl ethanolamide and sphingosine were decreased in the diabetic state. Treatment with hUCMSCs restored these metabolites to near-normal levels, thereby improving metabolic reprogramming and the vascular microenvironment. Correspondingly, endothelial cell proteomics revealed increased levels of glycolytic enzymes, inflammatory factors, and EndMT markers, including mitogen-activated protein kinase kinase kinase 20 (Map3k20), disintegrin and metalloproteinase domain-containing protein 10 (Adam10), and integrin alpha-8 (Itga8), in diabetes; hUCMSC treatment downregulated these factors. Notably, KEGG and protein-protein interaction analyses indicated that hUCMSCs inhibited the Tgfb1i1/Rock1 axis within the TGF-beta pathway, which drives EndMT. We further verified the expression of these proteins through endothelial immunofluorescent co-staining and confirmed the role of Rock1 in high glucose-induced EndMT in vitro. This study elucidates a potential molecular mechanism and a therapeutic strategy for early atherosclerosis in diabetes and provides a foundation for evaluating endothelial states in vivo.

Cellular reprogramming, a method of "resetting" the epigenetic clock by reversing the differentiation state of cells, has emerged as a promising approach to anti-aging, offering new strategies to slow down the aging process. Researchers convert differentiated cells into a pluripotent stem cell state through transcription factors or chemicals, restoring cellular youthfulness and regenerative capacity. This technology holds potential for tissue repair, lifespan extension, organ function improvement, and treatment of age-related diseases. In addition, cell reprogramming provides a novel pathway for disease modeling and drug screening, potentially accelerating the development and clinical application of anti-aging drugs. However, it faces challenges including safety, efficiency, and ethical considerations. This article focuses on the prospects of small-molecule-induced cell reprogramming for anti-aging, covering its mechanisms, applications, current limitations, and future directions to facilitate clinical translation and breakthroughs in human healthspan extension.

Background: Ulcerative colitis (UC), a chronic inflammatory gastrointestinal disease, is characterized by disrupted intestinal barrier integrity and unresolved endoplasmic reticulum (ER) stress, which drives epithelial apoptosis and disease progression. While mesenchymal stem cells (MSCs), particularly human umbilical cord-derived MSCs (hUC-MSCs), have shown therapeutic potential in UC, their mechanisms in modulating ER stress remain unclear. This study aimed to investigate the role of hUC-MSCs in alleviating ER stress-induced epithelial damage and elucidate the underlying molecular pathways in a murine colitis model and in vitro systems.

Results: Intraperitoneal administration of hUC-MSCs significantly attenuated dextran sulfate sodium (DSS)-induced colitis in mice. Histological analysis revealed restored crypt architecture and reduced epithelial apoptosis. Transcriptomic profiling demonstrated that hUC-MSCs reduced differentially expressed genes in inflammatory bowel disease-related and ER stress response pathways in colon tissues. Mechanistically, hUC-MSCs activated the IRE1/XBP1 axis, increasing Xbp1 splicing and suppressing pro-apoptotic Bcl2l11 expression. In vitro, hUC-MSC-conditioned medium protected colon epithelial cells from TNF-α-induced apoptosis via IRE1/XBP1 activation, an effect abolished by the IRE1 inhibitor 4μ8C.

Conclusions: Our findings demonstrate that hUC-MSCs alleviate UC by mitigating ER stress through IRE1-mediated Xbp1 splicing, thereby reducing epithelial apoptosis and promoting mucosal repair. This study provides a mechanistic foundation for MSC-based therapies targeting ER stress in inflammatory bowel diseases.

Introduction: Mesenchymal stem cell-derived exosomes have garnered considerable attention in regenerative medicine due to their non-immunogenicity, low infusion toxicity, easy accessibility, straightforward preservation, and minimal ethical concerns. While ultracentrifugation is the prevailing method for high-purity exosome isolation, it is limited by low throughput and the need for specialized infrastructure. This study investigates tangential flow filtration (TFF) as a promising alternative for exosome isolation. This technique offers simpler operation, higher yields, and improved recovery rates compared to ultracentrifugation.

Methods: Human umbilical cord mesenchymal stem cells (hUCMSCs) were cultured in a 3D microcarrier-bioreactor system, and exosomes were extracted from the conditioned medium using either ultracentrifugation or an automated and enclosed TFF system. Subsequently, we compared the quantity, quality and therapeutic efficacy of the exosomes isolated via both approaches, evaluating their effects in vitro and in a mouse model of diabetic wound healing.

Results: Our findings demonstrate that the TFF method effectively isolates high-quality exosomes that meet the standards set by the Minimum Information for Studies of Extracellular Vesicles (MISEV) 2023 guidelines, while achieving a significantly higher extraction yield compared to the traditional ultracentrifugation. Furthermore, both TFF and ultracentrifugation-derived exosomes demonstrate comparable biological activity in vitro and similar therapeutic potential for treating diabetic wound healing, potentially through promoting M2 macrophage polarization and angiogenesis.

Conclusion: The results indicate that TFF is a viable method for scalable and efficient exosome production, facilitating advancements in clinical applications for diabetic wound repair.

Background: Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome with a high mortality rate and limited therapeutic options. Macrophage efferocytosis plays an essential role in maintaining tissue homeostasis, and its dysfunction may be associated with the pathogenesis of ACLF. We previously found that mesenchymal stem cell (MSC) treatment in ACLF mice promoted macrophage M2 polarization and elevated the efferocytosis-related protein Mertk, but the underlying mechanisms remained unclear.

Methods: The role of efferocytosis was investigated in liver tissues from ACLF patients and an ACLF mouse model treated with MSC-derived exosomes (MSC-Exos). In vitro experiments utilizing lipopolysaccharide-induced M1 macrophages were conducted to dissect the underlying mechanism, targeting the miRNA let-7a-5p. Engineered exosomes (MSC-Exoslet-7a-5p) were developed via electroporation to validate the therapeutic potential.

Results: Impaired macrophage efferocytosis in liver tissues correlated with poor prognosis in ACLF patients. Treatment with MSC-Exos significantly improved histological morphology, liver function and enhanced efferocytosis in ACLF mice. Mechanistically, MSC-Exos delivered let-7a-5p to M1 macrophages, which downregulated Arid3a and upregulated Mertk expression. Furthermore, engineered MSC-Exoslet-7a-5p promoted efferocytosis more effectively than unmodified exosomes.

Conclusion: MSC-Exos enhance macrophage efferocytosis in ACLF via the let-7a-5p/Arid3a/Mertk axis. Engineered MSC-Exoslet-7a-5p, by boosting this pathway, provide a potential strategy for improving ACLF therapy.

Background: Stroke is a leading cause of death worldwide. Traditional treatments have limitations, stem cell therapy has potential for regeneration after ischemic stroke. This study evaluated the safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cell (UC-MSC) infusion via the intravenous (IV) and intrathecal (IT) routes for treating neurological sequelae after ischemic stroke.

Methods: This phase II randomized controlled trial involved 32 patients aged 40-75 years with neurological sequelae after ischemic stroke. The patients were randomly assigned into two groups: 16 received two IT UC-MSC infusions plus rehabilitation therapy, and 16 received two IV UC-MSC infusions plus rehabilitation therapy. Additionally, 16 matched controls, paired with the IT group by sex, age (±5 years), and NIHSS, received only rehabilitation. UC-MSCs were administered at 1.5 × 106 cells/kg at baseline and 3 months. Outcomes were assessed at baseline, 3, 6, and 12 months using NIHSS, FIM, MAS, FMS, and SF-36.

Results: No severe adverse events related to UC-MSC therapy were observed. Adverse event rate was lower in the IV group than the IT group. At 6 months, the IV group demonstrated significant improvements in NIHSS (p = 0.046), FIM (p = 0.028), and SF-36 (p < 0.001). At 12 months, both UC-MSC groups showed significant improvements, with greater effects in the IV group (p < 0.001 for SF-36).

Conclusion: Both IV and IT UC-MSC infusions improved neurological recovery and quality of life, with fewer adverse events in the IT group.

Trial registration: NCT05292625.