YAP promotes cardiomyocyte cell cycle entry

Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state. Overall design: We conditionally expressed a Yap isoform incapable of being phosphorylated by Lats1/2, YAP5SA, in CMs using a mouse model that we described previously (Monroe et al., 2019). We then performed cardiac Drop-seq on Myh6-MerCreMer/+; YAP5SA-tg/+ (hereafter referred to as YAP5SA) mice, in addition to control animals.