<p>Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and immunomodulatory properties; however, their therapeutic efficacy and underlying mechanisms in VaD remain incompletely understood. In this study, we investigated the effects of hUCB-MNCs treatment in a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Behavioral assessments showed that hUCB-MNCs treatment improved cognitive performance, affective-like behaviors, and motor coordination in BCAS mice. Histopathological analyses demonstrated that hUCB-MNCs treatment attenuated white matter injury, preserved myelin integrity, and mitigated neuronal and synaptic damage. Integrated transcriptomic and proteomic analyses of corpus callosum (CC) tissues revealed enrichment of immune-regulatory, phagocytosis-related, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-associated pathways after hUCB-MNCs treatment. In vivo and in vitro analyses further indicated that hUCB-MNCs helped preserve microglial homeostatic features and improved myelin debris-handling responses. Collectively, these findings suggest that hUCB-MNCs ameliorate VaD-associated pathology, at least in part, by modulating microglial myelin debris-handling responses and PI3K/AKT-related signaling, highlighting hUCB-MNCs as a promising cell-based therapeutic candidate for VaD.</p> Graphical Abstract <p></p>

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Human umbilical cord blood mononuclear cells ameliorate vascular dementia by modulating microglial myelin debris handling and white matter injury

  • Xueyi Wen,
  • Kejing He,
  • Cheng Huang,
  • Congying Shi,
  • Wei Wei,
  • Yusheng Zhang,
  • Zhenguo Yang,
  • Keshen Li

摘要

Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and immunomodulatory properties; however, their therapeutic efficacy and underlying mechanisms in VaD remain incompletely understood. In this study, we investigated the effects of hUCB-MNCs treatment in a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Behavioral assessments showed that hUCB-MNCs treatment improved cognitive performance, affective-like behaviors, and motor coordination in BCAS mice. Histopathological analyses demonstrated that hUCB-MNCs treatment attenuated white matter injury, preserved myelin integrity, and mitigated neuronal and synaptic damage. Integrated transcriptomic and proteomic analyses of corpus callosum (CC) tissues revealed enrichment of immune-regulatory, phagocytosis-related, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-associated pathways after hUCB-MNCs treatment. In vivo and in vitro analyses further indicated that hUCB-MNCs helped preserve microglial homeostatic features and improved myelin debris-handling responses. Collectively, these findings suggest that hUCB-MNCs ameliorate VaD-associated pathology, at least in part, by modulating microglial myelin debris-handling responses and PI3K/AKT-related signaling, highlighting hUCB-MNCs as a promising cell-based therapeutic candidate for VaD.

Graphical Abstract