Induced reprogramming of adult murine cardiomyocytes to pluripotency in vivo

Abstract

ABSTRACTPartial 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 trigger rejuvenation and/or augment regeneration of aged or injured tissues. In vivo reprogramming of adult mouse cardiomyocytes has been elusive, but success could overcome the lack of endogenous cardiomyocyte turnover that contributes to the poor resolution of heart disease. Here, we exploited cell type-specific Cre recombination and conditional, doxycycline-inducible, control of gene expression to generate cardiomyocyte-specific, inducible, reprogrammable mice. Eighteen days of doxycycline-induced OKSM expression in this model established a gene expression program characteristic of the pluripotent state and triggered the generation of teratomas of confirmed cardiomyocyte origin. These findings confirm that OKSM reprograms adult mouse cardiomyocytes to pluripotency and will enable studies of the contribution of reprogrammed cardiomyocytes to cardiac regeneration.