LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration

• 作者: Yahan Wu Liping Zhou Hongyu Liu Ran Duan Huixing Zhou Fulei Zhang Xiaoyu He Dongbo Lu Ke Xiong Maolin Xiong Jinzhu Zhuang Yi Liu Li Li Dandan Liang Yi-Han Chen
• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2021,（4）
• 所属期刊栏目: ARTICLES
• 页码范围: 450-462
• 页数: 13页
• 语种: 英文

摘要

The adult mammalian heart is thought to be a terminally differentiated organ given the postmitotic nature of cardiomyocytes.Consequently,the potential for cardiac repair through cardiomyocyte proliferation is extremely limited.Low-density lipoprotein receptor-related protein 6(LRP6)is a Wnt co-receptor that is required for embryonic heart development.In this study we investigated the role of LRP6 in heart repair through regulation of cardiomyocyte proliferation.Lrp6 deficiency increased cardiomyocyte cell cycle activity in neonatal,juvenile and adult mice.Cardiomyocyte-specific deletion of Lrp6 in the mouse heart induced a robust regenerative response after myocardial infarction(Ml),led to reduced Ml area and improvement in left ventricular systolic function.In vivo genetic lineage tracing revealed that the newly formed cardiomyocytes in Lrp6-deficient mouse hearts after Ml were mainly derived from resident cardiomyocytes.Furthermore,we found that the pro-proliferative effect of Lrp6 deficiency was mediated by the ING5/P21 signaling pathway.Gene therapy using the adeno-associated virus(AAV)9 miRNAi-Lrp6 construct promoted the repair of heart injury in mice.Lrp6 deficiency also induced the proliferation of human induced pluripotent stem cell-derived cardiomyocytes(iPSC-CMs).Our study identifies LRP6 as a critical regulator of cardiomyocyte proliferation,which may lead to the development of a novel molecular strategy to promote myocardial regeneration and repair.