Abstract 11339: Direct Reprogramming of Human Fibroblasts Toward the Cardiomyocyte Lineage
The direct reprogramming of adult cells into alternative cell types holds great promise for regenerative medicine. Recently, we reported that three developmental transcription factors_Gata4, Mef2c, and Tbx5 (GMT)_directly reprogrammed non-myocyte mouse heart cells into induced cardiomyocyte (CM)-like cells (iCMs) in vitro and in vivo. The human heart contains a vast pool of non-myocytes, mostly fibroblasts, which could be reprogrammed into iCMs; however, we found that GMT alone was insufficient in human fibroblasts, at least in vitro. Here, we show that GMT plus the transcription factors ESRRG and MESP1 induced global cardiac gene expression and phenotypic shifts in human fibroblasts. Addition of Myocardin and ZFPM2 further enhanced reprogramming, including improved sarcomere formation, calcium transients and action potentials. Reprogramming of fibroblasts toward a CM state was epigenetically stable. Analysis of orthologous gene expression indicated a comparable degree in in vitro reprogrammed human 7-factor iCMs and mouse GMT-iCMs; furthermore, in vivo reprogrammed mouse iCMs and mouse adult CMs had such similarity in global gene-expression that they were clustered into one group of cells. These findings demonstrate that human fibroblasts can be directly reprogrammed toward the cardiac lineage and lay the foundation for future refinement in vitro and testing in non-human primates in vivo.
- © 2013 by American Heart Association, Inc.