Novel Wnt potentiators induce iPSC-derived cardiomyocyte proliferation and increase embryonic zebrafish heart size.

Canonical Wnt/β-catenin pathway activation can promote cardiomyocyte (CM) cell cycle activity, but translation is limited by off-target and functional liabilities associated with global pathway activation. We identified two small molecules, LRN9 and DF6, which potentiate Wnt/β-catenin signaling through a non-GSK3β mechanism and induce CM cell-cycle re-entry in human iPSC-CMs. In cardiac organoids, the effects was largely restricted to CMs and were accompanied by minimal changes in contractile and relaxation parameters, in contrast to reported impairment with GSK3β inhibition. RNA-sequencing showed enrichment of DNA replication and cell-cycle pathways. In embryonic zebrafish, both compounds increased ventricular growth consistent with CM hyperplasia.