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Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity (RNA-Seq)

ABSTRACT: Diabetic cystopathy, affecting half of individuals with diabetes, often progresses to detrusor underactivity (DUA), a late and irreversible stage of bladder dysfunction. Despite its prevalence, the etiology of diabetic DUA remains elusive, with no established treatments. Mesenchymal stem cell (MSC) transplantation, demonstrated as a promising therapeutic avenue in preclinical studies, lacks comprehensive analyses of its mechanisms, tumorigenic risks, and optimal protocols for diabetic DUA. This study addresses these gaps, exploring transcriptome changes post-MSC treatment in a diabetic DUA preclinical model. Oxidative injury emerged as a significant pathological mechanism, with N-acetylcysteine (NAC) enhancing MSC synergistic effects, potentially reducing the amount of required MSCs . Additionally, human umbilical cord-derived MSCs with high antioxidant capacity (PFO-MSCs) exhibited improved and sustained therapeutic efficacy, integrating into myocytes within bladder muscle bundles or neighboring pericytes. Single-cell transcriptome analysis of engrafted cells revealed expression changes in pathways related to muscle development and immune responses, emphasizing the pivotal roles of cMET and PD-L1 in muscle regeneration and immune modulation within diabetic DUA. This study provides a comprehensive overview of the pathogenesis and repair processes following MSC therapy for diabetic DUA, enhancing our understanding of its mode of action, efficacy, and safety for future clinical applications.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE263322 | GEO | 2025/02/17

REPOSITORIES: GEO

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Project description:BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

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Mesenchymal stem cell with enhanced antioxidant capacity integrates into smooth muscle cells in diabetic detrusor underactivity (RNA-Seq)

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