北京大学熊敬维、雷晓光以及复旦大学赵世民研究团队合作发现一种小分子混合物可促进哺乳动物心肌细胞 (CM)增殖和心脏再生。相关论文于2022年4月7日发表在《细胞—干细胞》杂志上。

他们报告了一种促进成人 CM 增殖和心脏再生的五种小分子 (5SM) 的化学混合物。高含量化学筛选以及小分子相互作用的算法辅助预测，确定了有效诱导 CM 细胞周期重新进入的 5SM 5SM 的腹腔给药逆转了大鼠心肌梗死后心脏功能的丧失，诱导了 CM 增殖，并减少了心脏纤维化。从机制上讲，5SM 可能靶向 α1 肾上腺素能受体、JAK1、DYRKs、PTEN 和 MCT1，并与乳酸-LacRS2 信号传导相关，导致 CM 代谢在进入细胞周期之前转向糖酵解/生物合成和 CM 去分化。我们的工作阐明了对 CM 再生机制的理解，并为修复心脏开辟了治疗途径。

据介绍，斑马鱼和哺乳动物新生儿通过诱导内源性CM增殖具有强大的心脏再生能力，但成年哺乳动物心脏的再生潜力非常有限。开发用于诱导成年哺乳动物心脏再生的小分子的成功有限。

附：英文原文

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

Author: 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

Issue&Volume: 2022/04/07

Abstract: Zebrafish and mammalian neonates possess robust cardiac regeneration via the inductionof endogenous cardiomyocyte (CM) proliferation, but adult mammalian hearts have verylimited regenerative potential. Developing small molecules for inducing adult mammalianheart regeneration has had limited success. We report a chemical cocktail of fivesmall molecules (5SM) that promote adult CM proliferation and heart regeneration.A high-content chemical screen, along with an algorithm-aided prediction of small-moleculeinteractions, 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, 5SMpotentially targets α1 adrenergic receptor, JAK1, DYRKs, PTEN, and MCT1 and is connectedto lactate-LacRS2 signaling, leading to CM metabolic switching toward glycolysis/biosynthesisand CM de-differentiation before entering the cell-cycle. Our work sheds lights onthe understanding CM regenerative mechanisms and opens therapeutic avenues for repairingthe heart.

DOI: 10.1016/j.stem.2022.03.009

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00107-2