Hand factor ablation causes defective left ventricular chamber development and compromised adult cardiac function

Area of Science:

• Cardiovascular biology
• Developmental biology
• Molecular genetics

Background:

• Coordinated cardiomyocyte growth, differentiation, and morphogenesis are vital for heart formation.
• The bHLH transcription factors Hand1 and Hand2 are implicated in regulating these processes.

Purpose of the Study:

• To investigate the roles of Hand1 and Hand2 in left ventricle (LV) cardiomyocyte proliferation and morphogenesis.
• To explore the potential of removing defective myocardium for cardiac repair.

Main Methods:

• Utilized an LV-specific Cre allele (Hand1LV-Cre) to ablate Hand1-lineage cardiomyocytes.
• Performed conditional loss-of-function studies for both Hand1 and Hand2 in the LV.
• Assessed cardiac morphology, proliferation, and function in genetically modified embryonic hearts.

Main Results:

• Ablation of Hand1-lineage cardiomyocytes resulted in a hypoplastic LV, which showed recovery by E16.5.
• Loss-of-function of both Hand1 and Hand2 led to aberrant trabeculation and thickened compact zone myocardium due to enhanced proliferation and identity breakdown.
• Diminished cardiac function in Hand1;Hand2 mutants was rescued by concurrent ablation of Hand-null cardiomyocytes.

Conclusions:

• Hand1 and Hand2 are critical regulators of LV cardiomyocyte proliferation and morphogenesis.
• Removal of defective myocardium and replacement with healthy endogenous cardiomyocytes may be a viable strategy for cardiac repair.