PWMI后少突-血管单元重建对移植人少突胶质前体细胞成髓鞘的影响

少突胶质前体细胞（OPC）丢失及其分化失败导致髓鞘形成障碍是早产儿脑白质损伤(PWMI)的典型病理特征，目前尚无有效疗法，以OPC为基础的细胞替代治疗有望成为有效策略。我们以国际领先的技术优势获得人OPC并进行了PWMI后移植研究，但发现移植OPC成髓鞘效率很低。研究表明“少突-血管单元”不仅是OPC发育和血管新生的微环境，也是移植OPC赖以生存的“土壤”，损伤后OPC分化微环境可能由促进转为抑制；但PWMI后单元特征性改变、OPC分化抑制机制、“去抑制”及单元重建策略尚有待明确。本项目拟以转基因鼠和早产儿尸检样本为研究对象，利用双光子活体成像、蛋白组学和Crispr/Cas9等技术明确PWMI后单元的特征性改变；获得抑制OPC分化成髓鞘的关键靶点；阐明基质干细胞（MSC）及其外泌体和内皮祖细胞（EPC）是否通过靶点调控、单元重建和微环境改善促OPC成髓鞘；本研究有助于人OPC的转化研究。

Oligodendrocyte progenitor cell (OPC) loses and differentiation failure lead to dysmyelination which is the typical pathological features of preterm white matter injury (PWMI). Until now, no treatment has shown efficacy. Cell replacement therapy based on OPC is expected to become an effective strategy for PWMI. We have obtained the human OPC with the world’s leading technique and performed OPC transplant in PWMI anmimal model. However, we found that myelination rate is very low after OPC transplant. Previous studies indicated that “oligovascular unit” not only is an important microenviroment for OPC development and angiogenesis, but also is the “soil” for transplanted OPC survival. OPC differentiation microenviroment might be from promoting to inhibiting after PWMI. However, the typical pathological changes in “oligovascular unit”, the mechanisms for OPC differentiation inhibition, the strategies for OPC differentiation disinhibition and “oligovascular unit” restoration remain to be clarified. We intend to take transgenic mice and peterm autopsy sample as the object of the research, and use two-photon imaging, proteomics and Crispr/Cas9 gene editing technique, etc. to clarify the typical pathological changes in “oligovascular unit” after PWMI. Then the key function targets to inhibit OPC differentiation and myelination will be revealed. Moreover, it will be clarified whether marrow stromal cell (MSC) and MSC derived exosome and endothelial cell(EC) promote OPC differentiation and myelination by function targets regulation, “oligovascular unit” restoration and microenviroment improvement. The project will contibute to human OPC translational research: from basic research to clinical application.