A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration

Jianyong Du; Lixia Zheng; Peng Gao; Hang Yang; Wan-Jie Yang; Fusheng Guo; Ruqi Liang; Mengying Feng; Zihao Wang; Zongwang Zhang; Linlu Bai; Ye Bu; Shijia Xing; Wen Zheng; Xuelian Wang; Li Quan; Xinli Hu; Haosen Wu; Zhixing Chen; Liangyi Chen; Ke Wei; Zhe Zhang; Xiaojun Zhu; Xiaolin Zhang; Qiang Tu; Shi-Min Zhao; Xiaoguang Lei; Jing-Wei Xiong

doi:10.1016/j.stem.2022.03.009

A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration

Cell Stem Cell. 2022 Apr 7;29(4):545-558.e13. doi: 10.1016/j.stem.2022.03.009.

Authors

Jianyong Du¹, Lixia Zheng¹, Peng Gao², Hang Yang³, Wan-Jie Yang⁴, Fusheng Guo⁵, Ruqi Liang⁵, Mengying Feng⁶, Zihao Wang², Zongwang Zhang², Linlu Bai², Ye Bu⁷, Shijia Xing², Wen Zheng², Xuelian Wang², Li Quan², Xinli Hu², Haosen Wu⁸, Zhixing Chen², Liangyi Chen², Ke Wei⁶, Zhe Zhang⁸, Xiaojun Zhu¹, Xiaolin Zhang⁹, Qiang Tu³, Shi-Min Zhao¹⁰, Xiaoguang Lei¹¹, Jing-Wei Xiong¹²

Affiliations

¹ Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Academy for Advanced Interdisciplinary Studies, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China; PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China.
² Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Academy for Advanced Interdisciplinary Studies, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China.
³ State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Innovation Academy for Seed Design, Chinese Academy of Sciences, Beijing 100101, China and University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Obstetrics and Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
⁵ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
⁶ Shanghai East Hospital, Shanghai Institute of Stem Cell Research and Clinical Translation, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
⁷ PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China.
⁸ Division of Cardiac Surgery, the Third Hospital of Peking University, Beijing 100083, China.
⁹ Dizal Pharma, Shanghai 201203, China.
¹⁰ Obstetrics and Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address: zhaosm@fudan.edu.cn.
¹¹ Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: xglei@pku.edu.cn.
¹² Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, College of Future Technology, Academy for Advanced Interdisciplinary Studies, and State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China; PKU-Nanjing Institute of Translational Medicine, Nanjing 211800, China. Electronic address: jingwei_xiong@pku.edu.cn.

PMID: 35395187
DOI: 10.1016/j.stem.2022.03.009

Abstract

Zebrafish and mammalian neonates possess robust cardiac regeneration via the induction of endogenous cardiomyocyte (CM) proliferation, but adult mammalian hearts have very limited regenerative potential. Developing small molecules for inducing adult mammalian heart regeneration has had limited success. We report a chemical cocktail of five small molecules (5SM) that promote adult CM proliferation and heart regeneration. A high-content chemical screen, along with an algorithm-aided prediction of small-molecule interactions, identified 5SM that efficiently induced CM cell cycle re-entry and cytokinesis. Intraperitoneal delivery of 5SM reversed the loss of heart function, induced CM proliferation, and decreased cardiac fibrosis after rat myocardial infarction. Mechanistically, 5SM potentially targets α1 adrenergic receptor, JAK1, DYRKs, PTEN, and MCT1 and is connected to lactate-LacRS2 signaling, leading to CM metabolic switching toward glycolysis/biosynthesis and CM de-differentiation before entering the cell-cycle. Our work sheds lights on the understanding CM regenerative mechanisms and opens therapeutic avenues for repairing the heart.

Keywords: cardiomyocyte cytokinesis; cardiomyocyte proliferation; heart regeneration; high-content screen; lactate signaling; rats; small-molecule compounds.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Heart
Mammals
Myocardial Infarction* / drug therapy
Myocytes, Cardiac* / metabolism
Rats
Signal Transduction
Zebrafish