人多能干细胞定向分化心肌细胞的关键circRNAs筛选及其调控机制研究

Cardiovascular disease is the leading cause of human death. The loss of cardiomyocytes in myocardial infarction could finally lead to heart failure. Induced pluripotent stem cells (iPSCs), with the features of self-renewal and pluripotency, hold great promise for cell therapy in myocardial infarction. However, current issues such as cell purity and cell immaturity of iPSC-derived cardiomyocytes (iPSC-CMs) need to be resolved before clinical application. In order to solve the issues on iPSC-CMs for cardiac repair, the applicant has proposed three studies: (1) screening the key circRNAs in cardiomycyte differentiation of human induced pluripotent stem cells; (2) investigating circRNAs-involved regulatory network and pathway; and (3) demonstrating the efficacy and safety of the transplantation of iPSC-CMs with intervened circRNAs expression in infarcted heart. This project could discover the new regulatory mechanisms in cardiomyocyte differentiation of induced pluripotent stem cells, establish novel differentiation protocol, obtain optimized cardiomyocytes, and finally improve translational application of iPSC-CMs treatment for myocardial infarction.

心血管疾病是人类健康的头号杀手，其中心肌梗死引起心肌细胞丢失是导致心力衰竭和心血管病死亡率居于首位的主要原因。诱导多能干细胞（iPSCs）具有自我更新和分化潜能，是修复梗死心肌的理想种子细胞之一。如何提高iPSCs衍生心肌细胞（iPSC-CMs）的纯度和成熟度，是利用iPSCs修复心肌亟待解决的关键问题。借助申请人在理论知识储备、科研技术积累、前期实验总结、团队和技术平台建设方面的优势，本项目拟筛选关键circRNAs在人源iPSC-CMs分化过程中的功能；明确circRNAs参与iPSC-CMs分化和功能的调控网络；并验证差异表达circRNAs的iPSC-CMs再生修复心肌的安全性和有效性。本项目的顺利实施能够探索多能干细胞定向分化心肌细胞的新调控机制，开发更有效的iPSC-CMs分化新方法，获得优质的治疗种子细胞，进而加速iPSC-CMs再生修复坏死心肌的临床转化应用。

心血管疾病是人类健康的头号杀手，其中心肌梗死引起心肌细胞丢失是导致心力衰竭和心血管病死亡率居于首位的主要原因。诱导多能干细胞（iPSCs）具有自我更新和分化潜能，是修复梗死心肌的理想种子细胞之一。本项目利用高通量测序等方法，筛选人源iPSC-CMs分化过程中的关键circRNAs，包括circSLC8A1、circCACNA1D、circSPHKAP和circALPK2等，阐述其对心肌细胞功能影响；明确circRNAs-miRNAs-mRNAs核心通路参与iPSC-CMs分化和功能的调节；验证差异表达circRNAs的iPSC-CMs治疗心肌梗死效果。