Heart failure caused by the loss or dysfunction of cardiomyocytes affects millions of people and is the leading cause of mortality. Adult heart has limited regeneration capacity. Transplantation of cardiac progenitor cells generated from embryonic stem cells or induced pluripotent stem cells (iPSCs) is one theoretically plausible way to improve cardiac functions.

The direct conversion, or transdifferentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provides another approach for cardiac regeneration. However, genetic manipulations raise safety concerns and are thus not desirable in most clinical applications.

Prof. XIE’s group from Shanghai Institute of Materia Medica (SIMM) focuses on chemical-induced somatic cell reprogramming and transdifferentiation studies. This year, they reported that a chemical cocktail containing bromodeoxyuridine (BrdU) can generate iPSCs without any genetic factors (Cell Research, doi: 10.1038/cr.2015.96). Recently, they discovered the generation of spontaneously beating cardiomyocyte-like cells from mouse fibroblasts by using only 3-6 small molecule compounds. This finding was published online on 21 August 2015 (Cell Research, doi:10.1038/cr.2015.99).

These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Genetic lineage tracing confirms the fibroblast origin of these CiCMs. Further studies show the generation of CiCMs passes through a cardiac progenitor stage instead of a pluripotent stage. By passing the use of viral-derived factors, this proof of concept study lays a foundation for in vivo cardiac transdifferentiation with pharmacological agents and possibly safer treatment of heart failure.

Yanbin Fu, Chenwen Huang, two Ph.D. candidates from Tongji University and Dr. Xinxiu Xu, a staff member of SIMM, shared the first authorship. This work was supervised by Prof. Xin Xie, a Principle Investigator of SIMM, and the deputy director of the National Center for Drug Screening, and an Adjunct Professor of Tongji University. Her research is mainly focused on GPCR-based drug discovery and chemical biology of stem cells.

Dr. YANG Huangtian from Institute of Health Sciences (HIS) and Dr. GAO Zhaobin from SIMM also contribute their advice and technical support on electrophysiology study.

This work was supported by grants from Chinese Academy of Sciences, Ministry of Science and Technology of China, and the National Natural Science Foundation of China.

Abstract:

The direct conversion, or transdifferentiation, of non-cardiac cells into cardiomyocytes by forced expression of transcription factors and microRNAs provides promising approaches for cardiac regeneration. However, genetic manipulations raise safety concerns and are thus not desirable in most clinical applications. The discovery of full chemically induced pluripotent stem cells suggest the possibility of replacing transcription factors with chemical cocktails. Here, we report the generation of automatically beating cardiomyocyte-like cells from mouse fibroblasts using only chemical cocktails. These chemical-induced cardiomyocyte-like cells (CiCMs) express cardiomyocyte-specific markers, exhibit sarcomeric organization, and possess typical cardiac calcium flux and electrophysiological features. Genetic lineage tracing confirms the fibroblast origin of these CiCMs. Further studies show the generation of CiCMs passes through a cardiac progenitor stage instead of a pluripotent stage. Bypassing the use of viral-derived factors, this proof of concept study lays a foundation for in vivo cardiac transdifferentiation with pharmacological agents and possibly safer treatment of heart failure.

Keywords: transdifferentiation; cardiac reprogramming; cardiomyocyte; fibroblast; chemical cocktail; small molecule compounds

Correspondence: XIE Xin, Tel: +86-21-50801313/156

E-mail: xxie@simm.ac.cn

Original article: http://www.nature.com/cr/journal/vaop/ncurrent/full/cr201599a.html

Chemical Induction of Cardiac Reprogramming of Fibroblasts（Image by SIMM）