EBF1 Regulates Cardiac Development Through Fibroblast to Myocyte Signaling

The transcription factor early B-cell factor 1 (EBF1) plays critical developmental roles in numerous organ systems, including B-cells, kidney, bone, and heart. During cardiogenesis, cardiomyocyte expression of EBF1 is reportedly undetectable and its effects on myocyte development and proliferation are thought to reflect a non-cell autonomous mechanism, acting via intercellular communication from EBF1 expressing non-myocyte cells. Here, using single-cell transcriptional profiling, we confirm the absence of Ebf1 transcripts in cardiomyocytes. Furthermore, employing computational receptor-ligand interaction analysis of dissociated cells from wildtype and EBF1-deficient hearts, we show that loss of function of this pioneer transcription factor enhances fibroblast to myocyte signaling via the collagen-integrin pathway. Finally, we generated fibroblast-specific EBF1 knockout mice using a PDGFRα-Cre transgenic driver, and found a nearly identical phenotype to that of the generalized knockout, with runting, premature death, an increase in left ventricular relative wall thickness and cardiomyocyte hyperplasia. These findings provide further mechanistic insight into the non-cell autonomous mechanism of action of EBF1 in cardiac growth and development.