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Stem Cell Reports. 2013 Aug 22;1(3):235-47. doi: 10.1016/j.stemcr.2013.07.005. eCollection 2013.

Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state.

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Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA ; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA ; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA ; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.


Direct reprogramming of adult somatic cells into alternative cell types has been shown for several lineages. We previously showed that GATA4, MEF2C, and TBX5 (GMT) directly reprogrammed nonmyocyte mouse heart cells into induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. However, GMT alone appears insufficient in human fibroblasts, at least in vitro. Here, we show that GMT plus ESRRG and MESP1 induced global cardiac gene-expression and phenotypic shifts in human fibroblasts derived from embryonic stem cells, fetal heart, and neonatal skin. Adding Myocardin and ZFPM2 enhanced reprogramming, including sarcomere formation, calcium transients, and action potentials, although the efficiency remained low. Human iCM reprogramming was epigenetically stable. Furthermore, we found that transforming growth factor β signaling was important for, and improved the efficiency of, human iCM reprogramming. These findings demonstrate that human fibroblasts can be directly reprogrammed toward the cardiac lineage, and lay the foundation for future refinements in vitro and in vivo.

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