A miR-200b-Filamin A axis drives epicardial contribution to cardiogenesis.

The epicardium provides essential cellular and molecular cues required for proper cardiogenesis and cardiac repair. Epicardial-derived cells (EPDCs) play a pivotal role in establishing cardiac structure, contributing to coronary vasculature formation, connective tissue organization, and post-ischemic cardiac remodeling. During EPDC emergence, the epicardium must preserve a precise balance between cellular motility and epithelial integrity. However, the mechanisms determining why some epicardial cells undergo epithelial-to-mesenchymal transition to become EPDCs while others retain an epithelial state remain unclear. We show that miR-200b is expressed in a subset of epicardial cells during embryonic EPDC formation. Gain-and loss-of-function experiments reveal that miR-200b regulates the overall number of EPDCs by modulating the proportion of symmetric and asymmetric cell divisions. RNA pull-down coupled with RNA-seq, together with in vitro and ex vivo functional assays, identified filamin A (FLNA)-a key regulator of spindle positioning during asymmetric division-as a direct miR-200b target in epicardial cells. FLNA loss reduced asymmetric divisions, supporting its role in promoting this division mode. Overall, our study defines a miR-200b-FLNA axis that governs symmetric versus asymmetric division to control epicardial tissue dynamics during cardiogenesis. Additionally, altered miR-200b expression after myocardial infarction in mice and humans suggests a potential role post-MI.