Dynamic map illuminates Hippo-cMyc module crosstalk driving cardiomyocyte proliferation

Area of Science:

• Cardiovascular Biology
• Computational Biology
• Systems Biology

Background:

• Cardiomyocyte (CM) proliferation is vital for cardiac development and regeneration.
• Coordination of CM proliferation regulators remains poorly understood.

Purpose of the Study:

• To develop a computational model of the CM proliferation regulatory network.
• To identify key regulators and gain systems-level understanding of CM proliferation control.

Main Methods:

• Developed a computational network model with five modules (DNA replication, mitosis, cytokinesis, growth factor, Hippo pathway).
• Integrated 72 nodes and 88 reactions into the network.
• Validated model predictions against 81 independent experiments from literature.

Main Results:

• The model accurately predicted 91.35% of independent experimental outcomes.
• Predicted a crosstalk between the Hippo and growth factor modules via PI3K and cMyc upon YAP activation.
• Validated the YAP-cMyc axis experimentally in rat CMs and in mouse hearts.

Conclusions:

• The validated computational model provides a systems-level understanding of CM proliferation control.
• Identified a critical YAP-cMyc axis coordinating cell cycle activity for cardiac regeneration.
• The model predicts how individual regulators and modules interact to control CM proliferation.