中国科学院上海药物研究所谢欣等合作取得一项新成果。他们利用化学物质原位重编程小鼠心脏成纤维细胞为心肌细胞。这一研究成果于2024年6月18日发表在学术期刊《中国药理学报》上。

据介绍，心肌细胞是终末分化细胞，增殖和再生能力有限。心肌梗死等疾病导致心肌细胞大量死亡，是导致死亡的主要原因。先前的研究表明，通过强制表达心脏转录因子和microRNAs，心脏成纤维细胞可以在体外和体内被诱导转分化为心肌细胞。

他们之前的研究表明，在体外和体内，完整的化学混合物也可以诱导成纤维细胞向心肌细胞的转分化。随着组织清除技术的发展，在整个器官水平上可视化重编程成为可能。

本研究以两种遗传示踪小鼠为实验对象，研究了化学混合物CRFVPTM诱导原位成纤维细胞向心肌细胞转分化的作用，并利用CUBIC组织清除技术和3D成像技术在全心脏水平上观察了这种重编程。此外，单细胞RNA测序(scRNA-seq)证实携带示踪标记的心脏成纤维细胞产生心肌细胞。他们的研究证实了，小分子混合物在全心脏水平诱导原位成纤维细胞到心肌细胞重编程的使用，并提供了一种新的自然整合心肌细胞来帮助心脏再生的概念证明。

附：英文原文

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

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

Issue&Volume: 2024-06-18

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.

DOI: 10.1038/s41401-024-01308-6

Source: https://www.nature.com/articles/s41401-024-01308-6