调控人多能干细胞诱导分化为自我更新的视网膜祖细胞的机制研究

视网膜变性是一类致盲眼病, 应用视网膜祖细胞（RPC）或成熟视网膜色素上皮（RPE）细胞移植是极具前景的治疗手段，但是供体细胞的匮乏限制了其应用。因对RPC自我更新分子机制缺乏认识，尚未实现RPC的有效体外扩增。目前虽已建立了成熟的将人多能干细胞诱导分化为RPE细胞的分化体系，但在体外难以维持成熟表型，本课题将进一步深入研究实现此目标。我们在前期研究中通过生长因子和小分子化合物的组合实现了小鼠RPC细胞的自我更新。本课题拟在此体系基础上进行改进从而实现捕获、扩增人多能干细胞诱导分化获得的RPC细胞，并利用上述筛选手段实现PRC细胞体外的有效维持，并对诱导分化为RPC细胞过程中调控的关键信号通路的进行研究。并利用视网膜变性大鼠模型，评价两种细胞移植的疗效。本课题的顺利实施不仅能深入的认识RPC细胞自我更新和RPE细胞分化的分子基础，也有助于解决于解决眼科疾病细胞治疗的细胞来源问题。

Retinal degeneration is the leading vision loss in people. Retinal progenitor cells (RPC) or mature retinal epithelium (RPE) transplantation is very promising treatment. However, the critical shortage of transplantable cells is the major bottleneck of this therapy. Currently, our understanding to the self-renewal of RPC is still very limited, which significantly compromises our ability to expand the cells ex vivo. In addition, although RPE has been successfully generated from human pluripotent stem cells, it is still very hard to maintain its mature phenotype in vitro，we will study on this field furtherly in the project to maintain the mature phenotypes of RPE in vitro. In our previous study, we established a chemically defined condition for mouse RPC self-renewal through a reiterative growth factor and chemical screening. In this study, we will base on this condition system to capture and maintain the RPC generated during the differentiation of human pluripotent stem cells, and study on the key regulation mechanism during the induction. Then, RPC and RPE will be further characterized by transplanting the cells to retinal degeneration rat model to evaluate the therapeutic potential. This project will deepen our understanding to the mechanisms that governing RPC self-renewal and RPE terminal differentiation, also will provide renewable cell source of RPC and RPE for cell therapy of the eye disease.