Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric Show more
Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain. We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction. Show less