In vivo reprogramming and epigenetic rejuvenation of adult cardiomyocytes ameliorate heart failure in mice

ABSTRACT Partial cell reprogramming has been demonstrated in certain mouse tissues by in situ overexpression of Oct3/4 , Klf4 , Sox2 and cMyc (OKSM) transcription factors, and can induce rejuvenation and/or augment regeneration. Reprogramming of adult cardiomyocytes has been elusive until recently, but its success could help overcome the lack of endogenous regenerative capacity of the mammalian myocardium. Here, we generated cardiomyocyte-specific, doxycycline-inducible, reprogrammable mice and demonstrated that sustained OKSM induction reprograms cardiomyocytes fully into teratoma-forming pluripotent cells. However, we also showed that cyclic OKSM upregulation induces significant decrease of epigenetic age in the cardiomyocytes without de-differentiation or reacquisition of pluripotency. In mice with progressive heart failure, cardiomyocyte epigenetic rejuvenation correlated with stabilization of systolic heart function. These findings confirm that OKSM can reprogram adult mouse cardiomyocytes to different states depending on the duration of their expression, and provide further evidence that partially reprogrammed cardiomyocytes may contribute to ameliorate cardiac disease.