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 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.

In vivo reprogramming leads to premature death due to hepatic and intestinal failure

“…Alternatively, the generation of tissue-specific reprogrammable mouse models such as skeletal muscle-specific (Wang et al, 2021), heart-specific (Chen et al, 2021;de Lázaro et al, 2021) and liver-specific (Hishida et al, 2022), or the ectopic local expression of Yamanaka factors by using adeno-associated virus (Lu et al, 2020;Senis et al, 2018) have allowed to circumvent the negative consequences of organismal reprogramming.…”

“…In this line, to induce whole body expression of OSKM in the absence of side effects, researchers have commonly used short-term cyclic expression of the OSKM factors, such as 2 days (Browder et al, 2022; Ocampo et al, 2016) or 3 days (Rodriguez-Matellan et al, 2020) of doxycycline (1mg/ml) followed by 5 or 4 days withdrawal, or lower concentration of doxycycline (0.2 mg/ul) for 7 days (Chondronasiou et al, 2022). Alternatively, the generation of tissue-specific reprogrammable mouse models such as skeletal muscle-specific (Wang et al, 2021), heart-specific (Chen et al, 2021; de Lázaro et al, 2021) and liver-specific (Hishida et al, 2022), or the ectopic local expression of Yamanaka factors by using adeno-associated virus (Lu et al, 2020; Senis et al, 2018) have allowed to circumvent the negative consequences of organismal reprogramming. Unfortunately, although these protocols have been shown to be effective on improving the regeneration capacity of some specific organs and ameliorating some age-associated phenotypes, it appears that the short-term or mild induction of in vivo reprogramming is insufficient to induce significant systemic rejuvenation or extend the lifespan of wild type mice.…”