ESC-sEVs促进衰老hNSCs向功能性锥体神经元分化治疗血管性痴呆的机制研究

血管性痴呆（VD）严重威胁人类生命健康，切实改善VD相关性认知障碍是临床亟待解决的难题。既往工作证实海马区神经干细胞(hNSCs)的衰老状态是影响VD患者预后的关键因素，而胚胎干细胞源小细胞外囊泡(ESC-sEVs)可显著改善VD相关性认知障碍，其机制与促进衰老hNSCs神经再生有关。进一步研究发现Gata2及下游Wnt通路可能是调控衰老hNSCs向功能性锥体神经元分化的关键机制，而MEF2可能是ESCs-sEVs发挥调控Gata2的关键因子。据此，本项目拟调控Gata2及Wnt通路以明确其参与调节衰老hNSCs向功能性锥体神经元分化；干预MEF2以证实ESC-sEVs通过转运MEF2上调Gata2而促进VD衰老的hNSCs向功能性锥体神经元分化。最终阐明ESC-sEVs促进衰老的hNSCs分化为功能性锥体神经元治疗VD的作用和具体机制，为VD的治疗研究提供新的理论依据和技术策略。

Vascular dementia (VD) cause a severe threat to public health. However, how to improve the cognitive dysfunction resulted from VD is a critical and urgent question to be solved. Our previous study indicated that hippocampal neural stem cells (hNSCs) senescence played a key role in the prognosis of VD, and treatment with embryonic stem cells-derived small extracellular vesicles (ESC-sEVs) remarkably facilitated cognitive recovery after VD, likely by the promotion of self-renewal and neurogenesis in senescent hNSCs. Furthermore, we also found that Gata2 and the downstream Wnt pathway may be the crucial mechanism to regulate the differentiation of senescent hNSCs into functional pyramidal neurons, and MEF2 may be the key factor for ESC-sEVs to modulate the expression of Gata2. Accordingly, we will use gene reprogramming method to regulate the expression of Gata2 and Wnt signaling pathway to determine that Gata2 modulate the differentiation of senescent hNSCs into functional pyramidal neurons via Wnt signaling pathway, and prove that ESC-sEVs deliver MEF2 to promote the differentiation of senescent hNSCs into functional pyramidal neurons through the up-regulation of Gata2 by means of regulating MEF2 expression in ESC-sEVs. We aim to clarify that the function and specific mechanism of ESC-sEVs on the promotion of senescent hNSCs to differentiate into functional pyramidal neurons for VD treatment, which provide new theoretical foundation and technological strategy to VD therapy.