The loss of cardiomyocytes (CMs) during heart failure (HF) cannot be replaced by new CMs due to their limited proliferative capacity. Regenerating the failing heart by promoting CM cell-cycle re-entry has thus become a possible solution rigorously pursued. Some genes have been proven to promote endogenous CM proliferation, nearly always preceded by CM dedifferentiation, wherein terminally-differentiated CMs are reversed back initially to a less-matured status, preceding cell division. However, very little else is known about CM dedifferentiation, including the lack of robust molecular markers, the mechanisms driving it, whether it necessarily leads to CM proliferation, and the effect of CM dedifferentiation alone on cardiac function. Therefore, investigating CM dedifferentiation is of great significance. Here, we profiled genome-wide transcriptional changes and identified novel molecular markers during CM dedifferentiation. We used the established
in vitro
model where adult mouse CMs dedifferentiated and re-differentiated (DR) upon 2-week long culture, without detectable cell division. DR was evident by breakdown and rebuilding of sarcomeres, and differential regulation of cardiac fetal genes. Tracking the transcriptome change pointed to gene pathways involved in this process and potential markers of CM dedifferentiation. Another assumption is that transient induction of
Yamanaka
factors (
Oct4, Sox2, Klf4, Myc, OSKM
) induces CM dedifferentiation of CMs
in vivo
, since the four factors are themselves sufficient to induce pluripotency of human and mouse somatic cells. Our preliminary results show that CM-specific overexpression of
OSKM
using adeno-associated virus serotype 9 (AAV9) induced fetal-like hallmarks, down-regulation of sarcomeric genes, re-activation of cell cycle, reduced fatty acid utilization, and associated loss of cardiac function . Putative markers identified in the
in vitro
model was also validated to be upregulated in
OSKM
-overexpressed CMs. In conclusion, through 2 models of CM dedifferentiation, we have screened out potential novel markers and regulators of CM dedifferentiation which now requires further validation.
Therapeutic delivery of cyclin-A2 via recombinant adeno-associated virus serotype 9 restarts the myocardial cell cycle: An in vitro study
