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

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

Peking University
PKU-Nanjing Institute of Translational Medicine
CAS - Institute of Genetics and Developmental Biology
Obstetrics and Gynecology Hospital of Fudan University
Beijing National Laboratory for Molecular Sciences
Tongji University
Peking University
Dizal Pharmaceuticals

Research output: Contribution to journal › Article › peer-review

79 Scopus citations

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.

Original language	English
Pages (from-to)	545-558.e13
Journal	Cell Stem Cell
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2022.03.009
State	Published - 7 Apr 2022
Externally published	Yes

Keywords

cardiomyocyte cytokinesis
cardiomyocyte proliferation
heart regeneration
high-content screen
lactate signaling
rats
small-molecule compounds

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10.1016/j.stem.2022.03.009

Cite this

Du, J., Zheng, L., Gao, P., Yang, H., Yang, W. J., Guo, F., Liang, R., Feng, M., Wang, Z., Zhang, Z., Bai, L., Bu, Y., Xing, S., Zheng, W., Wang, X., Quan, L., Hu, X., Wu, H., Chen, Z., ... Xiong, J. W. (2022). A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration. Cell Stem Cell, 29(4), 545-558.e13. https://doi.org/10.1016/j.stem.2022.03.009

@article{6f03bd3c8e284ccaa42ad45afbc1f316,

title = "A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration",

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",

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

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2022",

month = apr,

day = "7",

doi = "10.1016/j.stem.2022.03.009",

language = "英语",

volume = "29",

pages = "545--558.e13",

journal = "Cell Stem Cell",

issn = "1934-5909",

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number = "4",

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Du, J, Zheng, L, Gao, P, Yang, H, Yang, WJ, Guo, F, Liang, R, Feng, M, Wang, Z, Zhang, Z, Bai, L, Bu, Y, Xing, S, Zheng, W, Wang, X, Quan, L, Hu, X, Wu, H, Chen, Z, Chen, L, Wei, K, Zhang, Z, Zhu, X, Zhang, X, Tu, Q, Zhao, SM, Lei, X & Xiong, JW 2022, 'A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration', Cell Stem Cell, vol. 29, no. 4, pp. 545-558.e13. https://doi.org/10.1016/j.stem.2022.03.009

TY - JOUR

T1 - A small-molecule cocktail promotes mammalian cardiomyocyte proliferation and heart regeneration

AU - Du, Jianyong

AU - Zheng, Lixia

AU - Gao, Peng

AU - Yang, Hang

AU - Yang, Wan Jie

AU - Guo, Fusheng

AU - Liang, Ruqi

AU - Feng, Mengying

AU - Wang, Zihao

AU - Zhang, Zongwang

AU - Bai, Linlu

AU - Bu, Ye

AU - Xing, Shijia

AU - Zheng, Wen

AU - Wang, Xuelian

AU - Quan, Li

AU - Hu, Xinli

AU - Wu, Haosen

AU - Chen, Zhixing

AU - Chen, Liangyi

AU - Wei, Ke

AU - Zhang, Zhe

AU - Zhu, Xiaojun

AU - Zhang, Xiaolin

AU - Tu, Qiang

AU - Zhao, Shi Min

AU - Lei, Xiaoguang

AU - Xiong, Jing Wei

PY - 2022/4/7

Y1 - 2022/4/7

N2 - 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.

AB - 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.

KW - cardiomyocyte cytokinesis

KW - cardiomyocyte proliferation

KW - heart regeneration

KW - high-content screen

KW - lactate signaling

KW - rats

KW - small-molecule compounds

UR - https://www.scopus.com/pages/publications/85127502828

U2 - 10.1016/j.stem.2022.03.009

DO - 10.1016/j.stem.2022.03.009

M3 - 文章

C2 - 35395187

AN - SCOPUS:85127502828

SN - 1934-5909

VL - 29

SP - 545-558.e13

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 4

ER -

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

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Keywords

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