YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo

Specialized adult somatic cells, such as cardiomyo- cytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying or- gan 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 mouseCMsto 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 accessi- bility and expression of fetal genes, partially reprog- ramming long-lived somatic cells in vivo to a primi- tive, fetal-like, and proliferative state.