2. Academic Validation
  3. In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals

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

  • Acta Pharmacol Sin. 2024 Nov;45(11):2290-2299. doi: 10.1038/s41401-024-01308-6.
Zi-Yang Chen 1 2,  Si-Jia Ji 1 2 3,  Chen-Wen Huang 1,  Wan-Zhi Tu 1 2 3,  Xin-Yue Ren 1 2,  Ren Guo 1 4,  Xin Xie 5 6 7 8 9
Affiliations

Affiliations

  • 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 State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 6 School of Pharmacy, University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China. [email protected].
  • 8 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264119, China. [email protected].
  • 9 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
PMID: 38890526 DOI: 10.1038/s41401-024-01308-6
Abstract

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.

Keywords

cardiac transdifferentiation; cardiomyocytes; fibroblasts; in situ transdifferentiation; in vivo transdifferentiation; small molecules.

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