Hemodynamic Forces Regulate Cardiac Regeneration-Responsive Enhancer Activity during Ventricle Regeneration

Area of Science:

• Cardiovascular Biology
• Regenerative Medicine
• Zebrafish Model Systems

Background:

• Vertebrate cardiac regenerative capacity differs significantly.
• Zebrafish exhibit robust heart regeneration, making them ideal models.
• Regeneration-responsive enhancers (RREs) are implicated in cardiac repair, but their activation mechanisms are unclear.

Purpose of the Study:

• To investigate the activation and regulation of a specific RRE during zebrafish heart regeneration.
• To elucidate the roles of hemodynamic forces and signaling pathways in controlling RRE activity.

Main Methods:

• Utilized transient and transgenic analysis in a larval zebrafish ventricle ablation model.
• Assessed enhancer activity (EGFP expression) linked to the *lepb*-linked enhancer sequence (LEN).
• Manipulated hemodynamic forces and mechanosensation pathways to study enhancer regulation.

Main Results:

• The *lepb*-linked enhancer sequence (LEN) drove EGFP expression during larval ventricle regeneration.
• Hemodynamic force alterations and mechanosensation pathway modulation attenuated LEN-driven EGFP expression.
• Notch signaling was found to influence endocardial LEN activity and endogenous *lepb* expression.

Conclusions:

• Established zebrafish models for efficient in vivo characterization of cardiac RREs.
• Demonstrated that hemodynamic forces and mechanosensation regulate enhancer activity during heart regeneration.
• Identified Notch signaling as a key regulator of enhancer function in cardiac repair.