Abstract 472: Cardiac Fibroblasts Regulate Myocardial Proliferation and Ventricular Formation through β1 Integrin Signaling
Ventricular cardiomyocyte proliferation is essential to support increasing hemodynamic demands during late cardiogenesis. The increase in thickness of the ventricle is achieved by greater proliferation in the compact myocardium than in the trabecular myocardium. Disruption of this process leads to a disease known as ventricular non-compaction. Although epicardial-derived signals may contribute to the proliferative process, the factors and cell types responsible for development of the compact layer are unclear. In particular, the function of embryonic cardiac fibroblasts, derivatives from epicardium, and their secreted factors are largely unknown. By analyzing cell markers, we found that cardiac fibroblasts appeared in the compact myocardium at embryonic day 12.5 and increased in number coincident with growth of the compact myocardium. Using a novel co-culture system, we found that embryonic cardiac fibroblasts were much more effective in inducing cardiomyocyte proliferation than adult cardiac fibroblasts. A genome-wide screen and siRNA knockdown experiments revealed that fibronectin and collagen were embryonic cardiac fibroblast-specific signals that promoted cardiomyocyte proliferation through β1 integrin signaling in primary culture. In vivo, cardiomyocyte expression of β1 integrin was upregulated as cardiac fibroblasts appeared in the heart and secreted extracellular matrix proteins. In agreement with a critical role for β1 integrin, cardiomyocyte-specific deletion of β1 integrin in mice resulted in reduced myocardial proliferation and ventricular compaction, with downregulation of cyclinD1 and cyclinE1 and upregulation of cyclinG2 and p21, leading to prenatal death. These findings demonstrate that cardiac fibroblasts regulate cardiomyocyte proliferation and ventricular compaction through extracellular matrix/β1 integrin signaling.