AUTHOR=Grivas Dimitrios , González-Rajal Álvaro , de la Pompa José Luis 

TITLE=Midkine-a Regulates the Formation of a Fibrotic Scar During Zebrafish Heart Regeneration

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.669439

DOI=10.3389/fcell.2021.669439

ISSN=2296-634X

ABSTRACT=<p>Unlike the hearts of mammals, the adult zebrafish heart regenerates after injury. Heart cryoinjury in zebrafish triggers the formation of a fibrotic scar that gradually degrades, leading to regeneration. Midkine-a (Mdka) is a multifunctional cytokine that is activated after cardiac injury. Here, we investigated the role of <italic>mdka</italic> in zebrafish heart regeneration. We show that <italic>mdka</italic> expression was induced at 1-day post-cryoinjury (dpci) throughout the epicardial layer, whereas by 7 dpci expression had become restricted to the epicardial cells covering the injured area. To study the role of <italic>mdka</italic> in heart regeneration, we generated <italic>mdka</italic>-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of <italic>mdka</italic> decreased endothelial cell proliferation and resulted in an arrest in heart regeneration characterized by retention of a collagenous scar. Transcriptional analysis revealed increases in collagen transcription and intense TGFβ signaling activity. These results reveal a critical role for <italic>mdka</italic> in fibrosis regulation during heart regeneration.</p>