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

被引：72

作者：

Du, Jianyong ^{[1
,2
,3
]}

Zheng, Lixia ^{[1
,2
,3
]}

Gao, Peng ^{[1
,2
]}

Yang, Hang ^{[4
]}

Yang, Wan-Jie ^{[5
,6
]}

Guo, Fusheng ^{[7
,8
]}

Liang, Ruqi ^{[7
,8
]}

Feng, Mengying ^{[9
]}

Wang, Zihao ^{[1
,2
]}

Zhang, Zongwang ^{[1
,2
]}

Bai, Linlu ^{[1
,2
]}

Bu, Ye ^{[3
]}

Xing, Shijia ^{[1
,2
]}

Zheng, Wen ^{[1
,2
]}

Wang, Xuelian ^{[1
,2
]}

Quan, Li ^{[1
,2
]}

Hu, Xinli ^{[1
,2
]}

Wu, Haosen ^{[10
]}

Chen, Zhixing ^{[1
,2
]}

Chen, Liangyi ^{[1
,2
]}

Wei, Ke ^{[9
]}

Zhang, Zhe ^{[10
]}

Zhu, Xiaojun ^{[1
,2
,3
]}

Zhang, Xiaolin ^{[11
]}

Tu, Qiang ^{[4
]}

Zhao, Shi-Min ^{[5
,6
]}

Lei, Xiaoguang ^{[7
,8
]}

Xiong, Jing-Wei ^{[1
,2
,3
]}

机构：

[1] Peking Univ, Beijing Key Lab Cardiometab Mol Med, Inst Mol Med, Coll Future Technol,Acad Adv Interdisciplinary St, Beijing 100871, Peoples R China

[2] Peking Univ, State Key Lab Nat & Biomimet Drugs, Nanjing 211800, Peoples R China

[3] PKU Nanjing Inst Translat Med, Nanjing 211800, Peoples R China

[4] Chinese Acad Sci, State Key Lab Mol Dev Biol, Inst Genet & Dev Biol, Innovat Acad Seed Design, Beijing 100101, Peoples R China

[5] Fudan Univ, Obstet & Gynecol Hosp, State Key Lab Genet Engn, Sch Life Sci, Shanghai 200032, Peoples R China

[6] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China

[7] Peking Univ, Beijing Natl Lab Mol Sci, Key Lab Bioorgan Chem & Mol Engn, Minist Educ,Dept Chem Biol,Coll Chem & Mol Engn, Beijing 100871, Peoples R China

[8] Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China

[9] Tongji Univ, Shanghai East Hosp, Sch Life Sci & Technol, Shanghai Inst Stem Cell Res & Clin Translat, Shanghai 200092, Peoples R China

[10] Peking Univ, Div Cardiac Surg, Hosp 3, Beijing 100083, Peoples R China

[11] Dizal Pharma, Shanghai 201203, Peoples R China

来源：

CELL STEM CELL | 2022年 / 29卷 / 04期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

CELL-CYCLE; C-KIT(+) CELLS; CARDIAC REGENERATION; MOSAIC ANALYSIS; DOUBLE MARKERS; REPAIR; PHOSPHATASE; INHIBITION; EXPRESSION; ALIGNMENT;

D O I：

10.1016/j.stem.2022.03.009

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 a1 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.

引用

页码：545 / +

页数：28

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