PUBLICATION
A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration
- Authors
- El-Sammak, H., Yang, B., Guenther, S., Chen, W., Marín-Juez, R., Stainier, D.Y.R.
- ID
- ZDB-PUB-220311-10
- Date
- 2022
- Source
- Circulation research 130(7): 1014-1029 (Journal)
- Registered Authors
- Chen, Wenbiao, Marín-Juez, Rubén, Stainier, Didier
- Keywords
- coronary vessels, endothelial cells, heart diseases, mammals, zebrafish
- Datasets
- GEO:GSE168175
- MeSH Terms
-
- Animals
- Cell Proliferation
- Endothelial Cells/metabolism
- Heart/physiology
- Mammals
- Myocytes, Cardiac/metabolism
- Regeneration/physiology
- Vascular Endothelial Growth Factor C*/metabolism
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 35264012 Full text @ Circ. Res.
Citation
El-Sammak, H., Yang, B., Guenther, S., Chen, W., Marín-Juez, R., Stainier, D.Y.R. (2022) A Vegfc-Emilin2a-Cxcl8a Signaling Axis Required for Zebrafish Cardiac Regeneration. Circulation research. 130(7):1014-1029.
Abstract
Background Ischemic heart disease following the obstruction of coronary vessels leads to the death of cardiac tissue and the formation of a fibrotic scar. In contrast to adult mammals, zebrafish can regenerate their heart after injury, enabling the study of the underlying mechanisms. One of the earliest responses following cardiac injury in adult zebrafish is coronary revascularization. Defects in this process lead to impaired cardiomyocyte repopulation and scarring. Hence, identifying and investigating factors that promote coronary revascularization holds great therapeutic potential.
Methods We used whole mount imaging, immunohistochemistry and histology to assess various aspects of zebrafish cardiac regeneration. Deep transcriptomic analysis allowed us to identify targets and potential effectors of Vegfc (vascular endothelial growth factor C) signaling. We used newly generated loss- and gain-of-function genetic tools to investigate the role of Emilin2a and Cxcl8a-Cxcr1 signaling in cardiac regeneration.
Results We first show that regenerating coronary endothelial cells upregulate vegfc upon cardiac injury in adult zebrafish and that Vegfc signaling is required for their proliferation during regeneration. Notably, blocking Vegfc signaling also significantly reduces cardiomyocyte dedifferentiation and proliferation. Using transcriptomic analyses, we identified emilin2a as an effector of Vegfc signaling and found that manipulation of emilin2a expression can modulate coronary revascularization as well as cardiomyocyte proliferation. Mechanistically, Emilin2a induces the expression of the chemokine gene cxcl8a in epicardium-derived cells, while cxcr1, the Cxcl8a receptor gene, is expressed in coronary endothelial cells. We further show that Cxcl8a-Cxcr1 signaling is also required for coronary endothelial cell proliferation during cardiac regeneration.
Conclusions These data show that after cardiac injury, coronary endothelial cells upregulate vegfc to promote coronary network reestablishment and cardiac regeneration. Mechanistically, Vegfc signaling upregulates epicardial emilin2a and cxcl8a expression to promote cardiac regeneration. These studies aid in understanding the mechanisms underlying coronary revascularization in zebrafish, with potential therapeutic implications to enhance revascularization and regeneration in injured human hearts.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping