Direct Reprogramming of Fibroblasts into Cardiomyocytes-A New Approach for Cardiac Regeneration

Abstract

Generating iPS cells by a combination of defined factors demonstrated that somatic cells can be induced to change their cell fate. Many fibroblasts exist in the post-natal heart, but no single master regulator of cardiac reprogramming has been identified. We postulated that not a single, but a combination of cardiogenic factors may reprogram fibroblasts into cardiomyocytes. We selected 14 candidate factors which are specifically expressed in embryonic cardiomyocytes and exhibited severe developmental cardiac defects and embryonic lethality when mutated. Among them, a combination of three developmental transcription factors rapidly and efficiently reprogrammed post-natal cardiac fibroblasts directly into cardiomyocytes. Induced cardiomyocytes expressed cardiac-specific proteins, exhibited a global gene expression profile and an epigenetic state similar to cardiomyocytes, and contracted spontaneously. Induced cardiomyocytes were not converted into the cardiac progenitor state for reprogramming, but rather they were directly reprogrammed into differentiated cardiomyocytes by defined factors. Moreover, fibroblast cells transplanted into mouse hearts one day after transduction of the three factors differentiated into cardiomyocytes in vivo. These findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming the vast pool of endogenous cardiac fibroblasts might provide a source of cardiomyocytes for regenerative therapies.