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LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration

Authors :
Maolin Xiong
Dandan Liang
Xiaoyu He
Jinzhu Zhuang
Fulei Zhang
Li Li
Yi Liu
Yi-Han Chen
Yahan Wu
Ran Duan
Ke Xiong
Dongbo Lu
Hongyu Liu
Liping Zhou
Huixing Zhou
Source :
Cell Res
Publication Year :
2020
Publisher :
Springer Science and Business Media LLC, 2020.

Abstract

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 (MI), led to reduced MI 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 MI 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.

Details

ISSN :
17487838 and 10010602
Volume :
31
Database :
OpenAIRE
Journal :
Cell Research
Accession number :
edsair.doi.dedup.....64cd97c890bbb046cdd333e7a4c4f7c3