The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of human cardiomyocytes

Cardiomyocyte (CM) proliferation and maturation are highly linked processes, however, the extent to which these processes are controlled by a single signaling axis is unclear. Here, we find the Hedgehog (HH)-GLI2-CKS1B cascade regulates the transition between proliferation and maturation in hiPSC-CMs. Initially, we found a significant enrichment of GLI2-signaling in CMs from patients with ischemic heart failure (HF) or dilated-cardiomyopathy (DCM), indicating initiation of fetal programs in the stressed heart. Developmentally, we showed downregulation of GLI-signaling in adult human CM, adult murine CM, and in late-stage hiPSC-CM. In early-stage, proliferative hiPSC-CM, inhibition of Hh- or GLI-proteins enhanced CM maturation. Mechanistically, we identified CKS1B, a new effector of GLI2 and showed that GLI2 binds the CKS1B promoter to regulate its expression. CKS1B overexpression in late-stage hiPSC-CMs led to increased proliferation with loss of maturation. Thus, the Hh-GLI2-CKS1B axis regulates the proliferation-maturation transition and provides targets to enhance cardiac tissue engineering and regenerative therapies.