MSCs胞外囊泡调控ENPC的SETD2/H3K36轴在糖尿病ENS重建中的作用及机制研究

糖尿病可引起广泛的肠神经系统(ENS)病变，临床表现包括糖尿病性胃轻瘫、肠功能障碍等，但目前尚无有效的治疗方法。我们前期研究发现：骨髓基质干细胞（MSCs）可促进糖尿病小鼠胃肠道动力恢复及ENS修复，但MSCs并非直接分化而是通过促进肠神经前体细胞（ENPC）向肠神经分化促进ENS修复。因此本研究旨在明确MSCs调控ENPC向肠神经分化的机制。本课题以糖尿病ENS病变为切入点，以MSCs/MSCs胞外囊泡为干预手段，结合前期“糖尿病小鼠肠道ENPC中SETD2表达特异性下调”及“MSCs-EVs分泌的HSP90可特异性调控SETD2的表达”两大原创性发现，拟构建ENPC示踪小鼠及SETD2敲除小鼠，通过探讨MSCs/MSCs胞外囊泡调控ENPC的SETD2/H3K36轴在糖尿病ENS重建中的作用及机制，为糖尿病ENS修复和胃肠动力障碍性疾病的治疗提供新线索。

Diabetes mellitus can cause a wide range of enteric nervous system (ENS) lesions, including diabetic gastroparesis, intestinal dysfunction, etc., but there is no effective treatment. Our previous study originally found that bone marrow mesenchymal stem cells (MSCs) can promote gastrointestinal motility recovery and ENS repair in diabetic mice, but not by directly differentiating into enteric nerves, but by promoting enteric nerve precursor cells (ENPC) to differentiate into enteric nerves. Therefore, this study aimed to identify the mechanism of MSCs regulating ENPC differentiation. This project took diabetic ENS lesions as the starting point and MSCs/MSCs extracellular vesicles as the intervention means, and combined with two previous original findings that "SETD2 expression in intestinal ENPC of diabetic mice is specifically down-regulated" and "HSP90 secreted by MSCs-EVs can specifically regulate SETD2 expression". In addition, ENPC lineage tracking mice and SETD2 knockout mice were constructed. By exploring the role and mechanism of the SETD2 /H3K36 axis of ENPC regulated by MSCs/MSCs extracellular vesicles in the remodeling of diabetic ENS, this study may provide new clues for the repair of diabetic ENS lesions and the treatment of gastrointestinal motility disorders.