Epicardial cell shape and maturation are regulated by Wt1 via transcriptional control of <i>Bmp4</i>

Abstract

The epicardium plays a crucial role in embryonic heart development and adult heart repair; however, the molecular events underlying its maturation remain unknown. <i>Wt1</i>, one of the main markers of the embryonic epicardium, is essential for epicardial development and function. Here, we analyse the transcriptomic profile of epicardial-enriched cells at different stages of development and from control and epicardial-specific <i>Wt1</i> knockout (<i>Wt1KO</i>) mice. Transcriptomic and cell morphology analyses of epicardial cells from epicardial-specific <i>Wt1KO</i> mice revealed a defect in the maturation process of the mutant epicardium, including sustained upregulation of <i>Bmp4</i> expression and the inability of mutant epicardial cells to transition into a mature squamous phenotype. We identified <i>Bmp4</i> as a transcriptional target of Wt1, thus providing a molecular basis for the retention of the cuboidal cell shape observed in the <i>Wt1KO</i> epicardium. Accordingly, inhibition of the Bmp4 signalling pathway both <i>ex vivo</i> and <i>in vivo</i> rescued the cuboidal phenotype of the mutant epicardium. Our findings indicate the importance of the cuboidal-to-squamous transition in epicardial maturation, a process regulated by Wt1.