肠神经（ENS）损伤目前尚缺乏有效治疗手段。我们前期报道显示骨髓基质干细胞（MSCs）是代偿性ENS神经再生的希望，然而再生肠神经元的分化程度、网络结构和功能修复仍明显不足。本课题基于“MSCs表型多态性”这一原创发现，充分利用“神经损伤高谷氨酸微环境与干细胞能量代谢”、“ eMSCs/fMSCs与MAPK/ERK差异性表达”这两个重要原创契合点，提出在神经损伤高谷氨酸特征性微环境下，MAPK/ERK通路可能通过差异性调控MSCs两亚群三羧酸循环能量代谢，改变细胞甲基化状态，从而差异性刺激两亚群的“类胶质细胞”特性，差异性诱导神经再生的观点。首次探讨eMSCs/fMSCs通过能量代谢在启动神经再生方面作用机制及效能的异同，为更优化地诱导ENS再生提供理论基础。MSCs是高度可塑的干细胞，强调微环境对MSCs生物学走向的影响，对整体认识MSCs在多种疾病中的临床价值及风险有重要提示意义。

Injury or neurodegenerative disorders of the enteric nervous system (ENS) cause gastrointestinal dysfunctions for which there is no effective therapy so far. Our previous study showed that bone marrow mesenchymal stem cells (MSCs) are considered as the hope of compensatory ENS nerve regeneration. However, the maturity, network structure and functional repair of regenerative intestinal neurons are still insufficient and are needed to be optimized. Our previous data have originally investigated that MSCs present as two different phenotypes in vitro: epithelial-like MSCs (eMSCs) and fibroblast-like MSCs (fMSCs) showing different characteristics of stem cell biology. However, the effect and mechanism of eMSCs/fMSCs on neuron regeneration remains unknown. The neuron injury could lead to the typical high glutamate microenvironment. Notably, the glutamate metabolism in tricarboxylic acid cycle (TCA cycle), which mainly regulated by MAPK/ERK signal, has been recently demonstrated to be involved in the regulation of methylation status of stem cells and further effects on stem cell biology. And most interesting, MAPK/ERK signal was differentially expressed in eMSCs/fMSCs. Therefore, we address the hypothesis that the differentially expressed MAPK/ERK signal in eMSCs/fMSCs could differentially progress to neuroregeneration through differential regulation of the tricarboxylic acid cycle metabolism, methylation status and "gliocyte-like" characteristics of eMSCs/fMSCs. The project aims to emphasis the differential regulation of metabolism on eMSCs/fMSCs in neuroregeneration under the typical high glutamate microenviroment of neuron injury. To understand the real pathophysiology regulation of microenviroment, metasbolism and phenotypes diversity of MSCs (eMSCs/fMSCs) in starting neuroregeneration holds the insightful therapeutic potential and optimizing clinical application for patients with gastrointestinal dismotility. The MSCs is a typical cell type with high plasticity. To emphasis the effects of disease-specific microenvironment on cell determination of MSCs helps to overall reveal the nature of biological characteristics of MSCs, and evaluate the benefits and risks of its application in different clinical diseases.