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Chemical Induction of Cardiac Reprogramming of Fibroblast

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


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