Journal
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2021.669439
Keywords
zebrafish heart regeneration; fibrotic scar; Midkine-a; signaling; signaling pathways; epicardium; collagen
Categories
Funding
- Spanish Ministry of Science, Innovation and Universities (MCIU) [PID2019-104776RB-I00, CB16/11/00399, RD16/0011/0021]
- Fundacion BBVA [BIO14_298]
- Fundacion La Marato [20153431]
- European Commission through CardioNeT from the European Commission [28600]
- European Regional Development Fund
- Instituto de Salud Carlos III (ISCIII)
- MCIU
- Pro CNIC Foundation
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Unlike mammalian hearts, adult zebrafish hearts can regenerate after injury. Mdka plays a critical role in fibrosis regulation during zebrafish heart regeneration, with loss of mdka resulting in decreased endothelial cell proliferation and an arrest in heart regeneration characterized by a collagenous scar. Increased collagen transcription and intense TGF beta signaling activity were also observed in mdka knockout zebrafish strains.
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 mdka in zebrafish heart regeneration. We show that mdka 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 mdka in heart regeneration, we generated mdka-knock out (KO) zebrafish strains. Analysis of injured hearts showed that loss of mdka 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 TGF beta signaling activity. These results reveal a critical role for mdka in fibrosis regulation during heart regeneration.
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