In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals  

作　　者：Zi-yang Chen Si-jia Ji Chen-wen Huang Wan-zhi Tu Xin-yue Ren Ren Guo Xin Xie 

机构地区：[1]State Key Laboratory of Drug Research,the National Center for Drug Screening,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,201203,China [2]School of Pharmacy,University of Chinese Academy of Sciences,Beijing,100049,China [3]School of Life Science and Technology,ShanghaiTech University,Shanghai,200031,China [4]Shandong Laboratory of Yantai Drug Discovery,Bohai Rim Advanced Research Institute for Drug Discovery,Yantai,264119,China [5]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou,310024,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2290-2299,共10页中国药理学报（英文版）

基　　金：supported by grants from the Ministry of Science and Technology of China(2022YFA1104700 and 2022ZD0204700 to XX);the National Natural Science Foundation of China(82121005 and 82330113 to XX,31900518 to CWH);Youth Innovation Promotion Association of the Chinese Academy of Sciences(2022280 to RG);Fundamental Research Projects of Science&Technology Innovation and Development Plan in Yantai City(2023JCYJ063 to RG);Taishan Scholars Program to XX.

摘　　要：Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate.Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death.Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs.Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo.With the development of tissue clearing techniques,it is possible to visualize the reprogramming at the whole-organ level.In this study,we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice,and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging.In addition,single-cell RNA sequencing(scRNA-seq)confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker.Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration.

关 键 词：cardiac transdifferentiation in situ transdifferentiation small molecules CARDIOMYOCYTES FIBROBLASTS in vivo transdifferentiation 

分 类 号：R542.2[医药卫生—心血管疾病]