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bioRxiv · 10.1101/2022.04.05.487243

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

Waldron, C. J.·Kelly, L.·Kawakami, Y.·Abrahante, J. E.·Magli, A.·Ogle, B. M.·Singh, B. N.
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Abstract

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.

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Waldron, C. J., Kelly, L., Kawakami, Y., Abrahante, J. E., Magli, A., Ogle, B. M., Singh, B. N.. 2022-04-08. The HH-GLI2-CKS1B network regulates the proliferation-to-maturation transition of human cardiomyocytes. https://doi.org/10.1101/2022.04.05.487243

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