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

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 succe...

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Veröffentlicht in:Cell stem cell 2022-04, Vol.29 (4), p.545
Hauptverfasser: Du, Jianyong, Zheng, Lixia, Gao, Peng, Yang, Hang, Yang, Wan-Jie, Guo, Fusheng, Liang, Ruqi, Feng, Mengying, Wang, Zihao, Zhang, Zongwang, Bai, Linlu, Bu, Ye, Xing, Shijia, Zheng, Wen, Wang, Xuelian, Quan, Li, Hu, Xinli, Wu, Haosen, Chen, Zhixing, Chen, Liangyi, Wei, Ke, Zhang, Zhe, Zhu, Xiaojun, Zhang, Xiaolin, Tu, Qiang, Zhao, Shi-Min, Lei, Xiaoguang, Xiong, Jing-Wei
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container_issue 4
container_start_page 545
container_title Cell stem cell
container_volume 29
creator Du, Jianyong
Zheng, Lixia
Gao, Peng
Yang, Hang
Yang, Wan-Jie
Guo, Fusheng
Liang, Ruqi
Feng, Mengying
Wang, Zihao
Zhang, Zongwang
Bai, Linlu
Bu, Ye
Xing, Shijia
Zheng, Wen
Wang, Xuelian
Quan, Li
Hu, Xinli
Wu, Haosen
Chen, Zhixing
Chen, Liangyi
Wei, Ke
Zhang, Zhe
Zhu, Xiaojun
Zhang, Xiaolin
Tu, Qiang
Zhao, Shi-Min
Lei, Xiaoguang
Xiong, Jing-Wei
description 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.
doi_str_mv 10.1016/j.stem.2022.03.009
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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. 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title A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration
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