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MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis

Lookup NU author(s): Nina Jordan, Dr Sam Tingle, Victoria Shuttleworth, Katie Cooke, Dr Rachael Redgrave, Dr Esha Singh, Emily Glover, Professor John Kirby, Professor Helen Arthur, Professor Christopher Ward, Professor Neil Sheerin, Professor Simi Ali

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

Abstract: In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Publication metadata

Author(s): Jordan NP, Tingle SJ, Shuttleworth VG, Cooke K, Redgrave RE, Singh E, Glover EK, Tajuddin HBA, Kirby JA, Arthur HM, Ward C, Sheerin NS, Ali S

Publication type: Article

Publication status: Published

Journal: International Journal of Molecular Sciences

Year: 2021

Volume: 22

Issue: 16

Print publication date: 02/08/2021

Online publication date: 11/08/2021

Acceptance date: 04/08/2021

Date deposited: 08/08/2021

ISSN (electronic): 1422-0067

Publisher: MDPI AG

URL: https://doi.org/10.3390/ijms22168629

DOI: 10.3390/ijms22168629


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