Neuropilin 1 mediates epicardial activation and revascularization in the regenerating zebrafish heart.

Unlike adult mammals, zebrafish can regenerate their heart. A key mechanism for regeneration is the activation of the epicardium, leading to the establishment of a supporting scaffold for new cardiomyocytes, angiogenesis and cytokine secretion. Neuropilins are co-receptors that mediate signaling of kinase receptors for cytokines with crucial roles in zebrafish heart regeneration. We investigated the role of neuropilins in response to cardiac injury and heart regeneration. All four neuropilin isoforms (, , and ) were upregulated by the activated epicardium and an -knockout mutant showed a significant delay in heart regeneration and displayed persistent collagen deposition. The regenerating hearts of mutants were less vascularized, and epicardial-derived cell migration and re-expression of the developmental gene was impaired. Moreover, cryoinjury-induced activation and migration of epicardial cells in heart explants were reduced in mutants. These results identify a key role for Nrp1 in zebrafish heart regeneration, mediated through epicardial activation, migration and revascularization.