β-catenin drives distinct transcriptional networks in proliferative and non-proliferative cardiomyocytes

The inability of the adult mammalian heart to regenerate represents a fundamental barrier in heart failure management. In contrast, the neonatal heart retains a transient regenerative capacity, but the underlying mechanisms are not fully understood. Wnt/β-catenin signaling has been suggested as a key cardio-regenerative pathway. Here, we show that Wnt/β-catenin signaling potentiates neonatal mouse cardiomyocyte proliferation in vivo and immature human pluripotent stem cell-derived cardiomyocyte (hPSC-CM) proliferation in vitro. In contrast, Wnt/β-catenin signaling in adult mice is cardioprotective but fails to induce cardiomyocyte proliferation. Transcriptional profiling of neonatal mouse and hPSC-CM revealed a core Wnt/β-catenin-dependent transcriptional network governing cardiomyocyte proliferation. In contrast, β-catenin failed to re-engage this proliferative gene network in the adult heart, which instead reverted to a neonatal-like glycolytic program. These findings suggest that Wnt/β-catenin drives distinct transcriptional networks in regenerative and non-regenerative cardiomyocytes, which may contribute towards the inability of the adult heart to regenerate following injury. 2D cardiac cells were treated with either 0.05% DMSO or 5 µM CHIR99021 for 24 hours and then sorted by FACS into cardiomyocyte (CD90-) and non-cardiomyocyte (CD90+) cell populations. Isolated cardiomycoytes from myocardial infarcted mice with AAV6 intramyocardial injections 2D cardiac cells were treated for 24 hours with 5 µm CHIR. hPSC-CMs were fixed for 10 minutes at room temperature with 1% paraformaldehyde (PFA). Cross-linking was stopped by addition 0.125M glycine for 5 minutes and ChIP-seq was performed