Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice

Abstract

Pluripotency factor drives cardiogenesis Research indicates that the adult mammalian heart does not contain cardiac stem cells and the vast majority of cardiomyocytes do not divide. Heart regeneration is thus limited after injury. The postmitotic nature of cardiomyocytes blocks cardiac tumor formation but at the same time minimizes cardiomyocyte renewal. Chen et al . report that cell type–specific expression of pluripotency factors dedifferentiates adult cardiomyocytes to a state that resembles fetal cardiomyocytes, enabling adult cardiomyocytes to reenter mitosis (see the Perspective by Wang and Blau). Cardiomyocytes can be reprogrammed to a pluripotent state when expression of pluripotency factors is sustained over an extended period. If cardiomyocytes are only partially reprogrammed, the heart regenerates without tumor formation. —BAP

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

“…The ability to reverse the fully differentiated state of adult mammalian cardiomyocytes to bona fide pluripotency is an important observation, since there is typically an inverse relationship between the differentiation status of a cell and its capacity to undergo reprogramming (Eminli et Our findings and those in a recent publication (Chen et al, 2021) suggest a new avenue for cardiac regeneration through cardiomyocyte reprogramming to a proliferative state. Chen and colleagues also demonstrated adult cardiomyocyte reprogramming to pluripotency, using a similar cardiomyocyte-specific reprogrammable mouse model (double mutant, and under the control of a different cardiomyocyte-specific promoter, by crossing the Myl2-Cre mouse with a conditional and inducible OKSM strain) (Chen et al, 2021). Their work also demonstrated that cardiomyocytes can be partially reprogrammed to a proliferative but not pluripotent state with a neonatal-like gene expression profile by limiting the duration of OKSM expression to 6 days, and that partial cardiomyocyte reprogramming is associated with an improvement of cardiac regeneration after myocardial infarction (Chen et al, 2021).…”

“…This possibility had remained elusive in earlier studies, likely due to a combination of low OKSM expression, poor temporal control over the latter, and use of viral vectors with promiscuous tropism to induce OKSM (Kisby et al, 2021a). The ability to reverse the fully differentiated state of adult mammalian cardiomyocytes to bona fide pluripotency is an important observation, since there is typically an inverse relationship between the differentiation status of a cell and its capacity to undergo reprogramming (Eminli et Our findings and those in a recent publication (Chen et al, 2021) suggest a new avenue for cardiac regeneration through cardiomyocyte reprogramming to a proliferative state. Chen and colleagues also demonstrated adult cardiomyocyte reprogramming to pluripotency, using a similar cardiomyocyte-specific reprogrammable mouse model (double mutant, and under the control of a different cardiomyocyte-specific promoter, by crossing the Myl2-Cre mouse with a conditional and inducible OKSM strain) (Chen et al, 2021).…”

“…Chen and colleagues also demonstrated adult cardiomyocyte reprogramming to pluripotency, using a similar cardiomyocyte-specific reprogrammable mouse model (double mutant, and under the control of a different cardiomyocyte-specific promoter, by crossing the Myl2-Cre mouse with a conditional and inducible OKSM strain) (Chen et al, 2021). Their work also demonstrated that cardiomyocytes can be partially reprogrammed to a proliferative but not pluripotent state with a neonatal-like gene expression profile by limiting the duration of OKSM expression to 6 days, and that partial cardiomyocyte reprogramming is associated with an improvement of cardiac regeneration after myocardial infarction (Chen et al, 2021). This approach adds to other gene therapies also proposed to stimulate endogenous cardiomyocyte proliferation, including those leveraging cell cycle regulators such as Cyclin D2 (Shapiro et al, 2014), metabolic regulators such as ERRB2 (D'Uva et al, 2015) or non-coding RNAs that regulate cardiomyocyte regeneration in other species (Aguirre et al, 2014).…”

OSKM-mediated reversible reprogramming of cardiomyocytes regenerates injured myocardium

“…al, the authors explore the possibility of reverting murine adult cardiomyocytes into a more immature state by forced-expression of OSKM factors (Oct4, Sox2, Klf4, and c-Myc) in murine cardiomyocytes, and investigate whether this reversion process allows resident cardiomyocytes to proliferate post-myocardial infarction (Chen et. al 2021 ). This de-differentiation reprogramming strategy resulted in decreased scar formation post-myocardial infarction, and demonstrated the potential for improving adult cardiomyocyte proliferative capacity by changing their maturation state through transient expression of OSKM in cardiomyocytes.…”

Transient reprogramming primes the heart for repair

“…Cellular reprogramming via the four pluripotency factors, OCT4, SOX2, KLF4, and MYC (OSKM), is a promising approach to epigenetically remodel somatic cells of various lineages into an induced pluripotent stem cell state. Partial reprogramming (PR) via the transient introduction of OSKM reverses age-associated phenotypes and promotes the regenerative potential of adult tissues such as skeletal muscle [2] . In an effort to illustrate the myocardial therapeutic significance of PR, Chen et al [3] , demonstrated that short-term myocardial introduction of OSKM reprograms cardiomyocytes to a fetal phenotype evidenced by (1) transcriptome resembling neonatal and embryonic developmental stages; (2) expression of α-SMA; and (3) morphological rearrangement and cell cycle re-entry in vitro.…”