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

Area of Science:

• Cardiovascular Biology
• Cell Signaling
• Developmental Biology

Background:

• Cardiomyocyte (CM) proliferation and maturation are critical for heart development and repair, but the regulatory mechanisms are not fully understood.
• Identifying key signaling pathways that govern the balance between CM proliferation and maturation is essential for advancing cardiac regenerative medicine.

Purpose of the Study:

• To elucidate the role of the Hedgehog (HH)-GLI2-CKS1B signaling cascade in regulating the transition between cardiomyocyte proliferation and maturation.
• To investigate the potential of targeting this pathway for therapeutic applications in cardiac tissue engineering and regenerative therapies.

Main Methods:

• Investigated the HH-GLI2-CKS1B pathway in various cardiomyocyte models, including adult human and murine CMs, and human induced pluripotent stem cell-derived CMs (hiPSC-CMs) at different developmental stages.
• Utilized gene inhibition and overexpression techniques to assess the impact on CM proliferation and maturation markers.
• Analyzed patient heart disease datasets to determine the relevance of GLI2 signaling in pathological conditions like heart failure (HF) and dilated cardiomyopathy (DCM).

Main Results:

• Downregulation of GLI signaling promotes maturation in adult and late-stage hiPSC-CMs.
• Inhibition of HH or GLI proteins in early-stage hiPSC-CMs enhanced maturation indices, calcium handling, and transcriptome.
• Identified CKS1B as a novel effector of GLI2 in CMs, where GLI2 regulates CKS1B expression; CKS1B overexpression promoted proliferation and inhibited maturation.
• GLI2 signaling was significantly enriched in patient datasets for ischemic heart failure and dilated cardiomyopathy.

Conclusions:

• The Hh-GLI2-CKS1B axis is a key regulator of the proliferation-maturation switch in cardiomyocytes.
• This pathway represents a promising target for enhancing cardiac tissue engineering and regenerative therapies by modulating cardiomyocyte behavior.