红系祖细胞通过外泌体介导代谢重组抑制脑梗死后神经毒性星形胶质细胞形成

脑梗死后大量的骨髓及外周细胞快速涌入颅内，对脑梗死的病程产生重要影响。明确外来细胞的种类及功能对于建立新的脑梗死治疗方法意义重大。近期研究提示红系祖细胞（EPCs）在肿瘤中具有免疫抑制作用，但在其他疾病中的作用尚不清楚。我们的预实验发现脑梗死促使大量EPCs聚集于颅内。其绝对数目明显多于其他外来细胞。耗竭EPCs导致梗死体积及死亡率明显增加，并显著改变了星型胶质细胞（AS）的代谢模式和诱导了神经毒性AS（A1）的形成。体外实验表明EPCs分泌大量外泌体且主要进入AS胞体。据此设想：EPCs通过外泌体影响AS的代谢并抑制A1形成促进脑梗死后的神经修复。为此，本研究拟利用EPCs、AS、脑梗死小鼠，采用高通量测序、代谢组学、荧光素酶基因报告实验、行为及形态评价学等方法和技术手段证实EPCs在脑梗死中的作用，揭示EPCs通过其外泌体调控AS代谢和抑制A1形成的分子机制，为脑梗死的治疗提供新思路。

A large amount of bone marrow and peripheral cells rapidly invade the brain after ischemic stroke， which has an important impact on the course of stroke. Defining the types and functions of foreign cells is of great significance for the establishment of new treatment methods for stroke. Recent studies suggest that erythroid progenitor cells (EPCs) have immunosuppressive effects in tumors, but the role in other diseases remains unclear. Our preliminary experiments found that ischemic stroke caused a large number of EPCs to accumulate in the brain. The absolute number was significantly higher than other foreign cells. Depletion of EPCs resulted in a significant increase in infarct volume and mortality, and significantly altered the metabolic pattern of astrocyte (AS) and induced the formation of neurotoxic AS (A1). In vitro experiments have shown that EPCs secrete a large number of exosomes that mainly enter the AS cell body. We hypothesize that EPCs promote the neurological repair by inhibiting the formation of A1 through their exosome- mediated metabolic reprogramming. In the project, we intend to utilize EPCs, AS, mice model of stroke to confirm the role of EPCs in stroke with high-throughput sequencing, metabolomics, luciferase gene reporting experiments, behavioral and morphological evaluation and so on. The molecular mechanism of EPCs regulating AS metabolism and inhibiting the formation of A1 through their exosomes will be clarified, which will help to provide a new idea for the development of stroke treatment.