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

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.
Jianyong Du 1,  Lixia Zheng 1,  Peng Gao 2,  Hang Yang 3,  Wan-Jie Yang 4,  Fusheng Guo 5,  Ruqi Liang 5,  Mengying Feng 6,  Zihao Wang 2,  Zongwang Zhang 2,  Linlu Bai 2,  Ye Bu 7,  Shijia Xing 2,  Wen Zheng 2,  Xuelian Wang 2,  Li Quan 2,  Xinli Hu 2,  Haosen Wu 8,  Zhixing Chen 2,  Liangyi Chen 2,  Ke Wei 6,  Zhe Zhang 8,  Xiaojun Zhu 1,  Xiaolin Zhang 9,  Qiang Tu 3,  Shi-Min Zhao 10,  Xiaoguang Lei 11,  Jing-Wei Xiong 12
Affiliations

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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.

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