The Extracellular Matrix Protein Agrin is Essential for Epicardial Epithelial-to-mesenchymal Transition During Heart Development

Overview

Journal Development

Specialty Biology

Date 2021 May 10

PMID 33969874

Citations 17

Authors

Xin Sun

Sophia Malandraki-Miller

Tahnee Kennedy

Elad Bassat

Konstantinos Klaourakis

Jia Zhao

Elisabetta Gamen

Joaquim Miguel Vieira

Eldad Tzahor

Paul R Riley

Affiliations

Soon will be listed here.

Abstract

During heart development, epicardial cells residing within the outer layer undergo epithelial-mesenchymal transition (EMT) and migrate into the underlying myocardium to support organ growth and morphogenesis. Disruption of epicardial EMT results in embryonic lethality, yet its regulation is poorly understood. Here, we report epicardial EMT within the mesothelial layer of the mouse embryonic heart at ultra-high resolution using scanning electron microscopy combined with immunofluorescence analyses. We identified morphologically active EMT regions that associated with key components of the extracellular matrix, including the basement membrane-associated proteoglycan agrin. Deletion of agrin resulted in impaired EMT and compromised development of the epicardium, accompanied by downregulation of Wilms' tumor 1. Agrin enhanced EMT in human embryonic stem cell-derived epicardial-like cells by decreasing β-catenin and promoting pFAK localization at focal adhesions, and promoted the aggregation of dystroglycan within the Golgi apparatus in murine epicardial cells. Loss of agrin resulted in dispersal of dystroglycan in vivo, disrupting basement membrane integrity and impairing EMT. Our results provide new insights into the role of the extracellular matrix in heart development and implicate agrin as a crucial regulator of epicardial EMT.

Citing Articles

Role of Agrin in tissue repair and regeneration: From mechanisms to therapeutic opportunities (Review).

Li X, Xu Y, Si J, Gu F, Ma Y Int J Mol Med. 2024; 54(5).

PMID: 39301653 PMC: 11410309. DOI: 10.3892/ijmm.2024.5422.

Epicardial EMT and cardiac repair: an update.

Foglio E, DAvorio E, Nieri R, Russo M, Limana F Stem Cell Res Ther. 2024; 15(1):219.

PMID: 39026298 PMC: 11264588. DOI: 10.1186/s13287-024-03823-z.

Exploring the Function of Epicardial Cells Beyond the Surface.

Wong D, Martinez J, Quijada P Circ Res. 2024; 135(2):353-371.

PMID: 38963865 PMC: 11225799. DOI: 10.1161/CIRCRESAHA.124.321567.

Epicardium and Coronary Vessels.

Ruiz-Villalba A, Guadix J, Perez-Pomares J Adv Exp Med Biol. 2024; 1441:155-166.

PMID: 38884710 DOI: 10.1007/978-3-031-44087-8_8.

Protein glycosylation in cardiovascular health and disease.

Chatham J, Patel R Nat Rev Cardiol. 2024; 21(8):525-544.

PMID: 38499867 DOI: 10.1038/s41569-024-00998-z.

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