Lymphatics-epicardial cross talk via Reelin controls cardiac growth.

How mammalian organ size is precisely regulated remains incompletely understood. This process depends on the coordinated balance between cell proliferation, differentiation, and apoptosis. In the heart, the epicardium plays a central role in embryonic cardiac growth as a source of multiple cardiac progenitor lineages. The transcription factor Wt1 is essential for epicardial development and maturation, and its loss disrupts epicardial maintenance and the generation of epicardial-derived cells (EPDCs). In addition, the epicardium produces mitogenic factors required for cardiomyocyte (CM) proliferation, including those of the insulin-like growth factor (IGF) signaling pathway. Consistently, functional inactivation of Igf1 or Igf2 in mice results in severe prenatal growth reduction, with mutant embryos ∼60% smaller than controls, underscoring the roles of these genes in organ and fetal growth. We recently identified the cardiac lymphatic vasculature as an unexpected regulator of heart size during embryonic development. Here, by combining single-cell RNA sequencing with loss-of-function mouse models, we uncover a critical regulatory network linking cardiac lymphatics, the epicardium, Wt1, and Igf1 signaling that controls the final stages of embryonic cardiac growth. Our findings suggest that cardiac lymphatics act as a physiological quality control system for heart growth. Furthermore, using gain-of-function approaches in human epicardial organoids, we demonstrate that Reelin promotes epicardial fate, suggesting that the beneficial roles of lymphatics in adult cardiac repair are likely mediated through Reelin-dependent epicardial reactivation.