Abstract
Coordinated cardiomyocyte growth, differentiation, and morphogenesis are essential for heart formation. We demonstrate that the bHLH transcription factors Hand1 and Hand2 play critical regulatory roles for left ventricle (LV) cardiomyocyte proliferation and morphogenesis. Using an LV-specific Cre allele (Hand1LV-Cre), we ablate Hand1-lineage cardiomyocytes, revealing that DTA-mediated cardiomyocyte death results in a hypoplastic LV by E10.5. Once Hand1-linage cells are removed from the LV, and Hand1 expression is switched off, embryonic hearts recover by E16.5. In contrast, conditional LV loss-of-function of both Hand1 and Hand2 results in aberrant trabeculation and thickened compact zone myocardium resulting from enhanced proliferation and a breakdown of compact zone/trabecular/ventricular septal identity. Surviving Hand1;Hand2 mutants display diminished cardiac function that is rescued by concurrent ablation of Hand-null cardiomyocytes. Collectively, we conclude that, within a mixed cardiomyocyte population, removal of defective myocardium and replacement with healthy endogenous cardiomyocytes may provide an effective strategy for cardiac repair.
Highlights
IntroductionBecause the left ventricle (LV) must be large enough to support adequate cardiac output but not hypertrophic or hypoplastic, such that it obstructs blood flow, congenital heart defects (CHDs) and acquired diseases that impact LV morphology or cell number present a significant cause of morbidity and mortality in the human population [1]
The left ventricle (LV) of the heart drives systemic circulation
Unlike in the adult heart, the embryonic left ventricle is remarkably tolerant of cell death, as remaining cells have the capacity to proliferate and to restore heart function
Summary
Because the LV must be large enough to support adequate cardiac output but not hypertrophic or hypoplastic, such that it obstructs blood flow, congenital heart defects (CHDs) and acquired diseases that impact LV morphology or cell number present a significant cause of morbidity and mortality in the human population [1]. These CHDs include left ventricular noncompaction or hypertrabeculation (LVNC; OMIM: 604169), which is a cardiomyopathy characterized by prominent trabeculations occluding the ventricular lumen and associated with a high risk of heart failure and sudden death [2, 3] and hypoplastic left heart syndrome (HLHS; OMIM: 614435), which presents an underdeveloped LV unable to sustain sufficient blood flow [4, 5]. Cre-loxP technology has been used to great effect in mice to genetically model SHF myocardium defects, the genetic tools to interrogate genetic loss-of-function in LV cardiomyocytes have, far, not been available
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