Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined Factors

SummaryThe reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) raises the possibility that a somatic cell could be reprogrammed to an alternative differentiated fate without first becoming a stem/progenitor cell. A large pool of fibroblasts exists in the postnatal heart, yet no single “master regulator” of direct cardiac reprogramming has been identified. Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c, and Tbx5) rapidly and efficiently reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Fibroblasts transplanted into mouse hearts one day after transduction of the three factors also differentiated into cardiomyocyte-like cells. We believe these findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming of endogenous or explanted fibroblasts might provide a source of cardiomyocytes for regenerative approaches.PaperClip To listen to this audio, enable JavaScript on your browser. However, you can download and play the audio by clicking on the icon belowHelp with MP3 filesOptionsDownload audio (2581 K)

Graphical AbstractFigure optionsDownload high-quality image (85 K)Download as PowerPoint slideHighlights
► Gata4/Mef2c/Tbx5 directly reprogram fibroblasts into cardiomyocyte-like cells
► Induced cardiomyocytes (iCMs) have spontaneous contraction and action potentials
► iCMs resemble cardiomyocytes in their global gene expression and epigenetic state
► Transplanted cardiac fibroblasts can be reprogrammed into iCMs in vivo