Volume 31, No 4, Apr 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 4, April 2021: 450-462   |  Open Access

ORIGINAL ARTICLES

LRP6 downregulation promotes cardiomyocyte proliferation and heart regeneration

Yahan Wu^1,2,3 , Liping Zhou^1,2,3 , Hongyu Liu^1,2,3 , Ran Duan^1,2,3 , Huixing Zhou^1,2,3 , Fulei Zhang^1,2,3 , Xiaoyu He^1,2,3 , Dongbo Lu^2,4 , Ke Xiong^1,2,3 , Maolin Xiong^2,4 , Jinzhu Zhuang^2,4 , Yi Liu^1,2 , Li Li^1,2,3,5,6 , Dandan Liang^1,2,3,6,* , Yi-Han Chen^1,2,3,5,6,*

¹Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China
²Key Laboratory of Arrhythmias of the Ministry of Education of China, Tongji University School of Medicine, Shanghai 200120, China
³Institute of Medical Genetics, Tongji University, Shanghai 200092, China
⁴Jinzhou Medical University, Jinzhou, Liaoning 121000, China
⁵Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai 200092, China
⁶Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing 100730, China
These authors contributed equally: Yahan Wu, Liping Zhou, Hongyu Liu, Ran Duan Correspondence: Dandan Liang(dandanliang@tongji.edu.cn)Yi-Han Chen(yihanchen@tongji.edu.cn)

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.

https://doi.org/10.1038/s41422-020-00411-7

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