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Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice

The current study evaluated the role of Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT) and its impact on radiation-induced tissue damage in mice. Phenotypic modifications of irradiated, Hey2 siRNA- and Hey2 vector plasmid-transfected human umbilical vei...

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Autores principales: Mintet, Elodie, Lavigne, Jérémy, Paget, Vincent, Tarlet, Georges, Buard, Valérie, Guipaud, Olivier, Sabourin, Jean-Christophe, Iruela-Arispe, Maria-Luisa, Milliat, Fabien, François, Agnès
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503994/
https://www.ncbi.nlm.nih.gov/pubmed/28694461
http://dx.doi.org/10.1038/s41598-017-05389-8
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author Mintet, Elodie
Lavigne, Jérémy
Paget, Vincent
Tarlet, Georges
Buard, Valérie
Guipaud, Olivier
Sabourin, Jean-Christophe
Iruela-Arispe, Maria-Luisa
Milliat, Fabien
François, Agnès
author_facet Mintet, Elodie
Lavigne, Jérémy
Paget, Vincent
Tarlet, Georges
Buard, Valérie
Guipaud, Olivier
Sabourin, Jean-Christophe
Iruela-Arispe, Maria-Luisa
Milliat, Fabien
François, Agnès
author_sort Mintet, Elodie
collection PubMed
description The current study evaluated the role of Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT) and its impact on radiation-induced tissue damage in mice. Phenotypic modifications of irradiated, Hey2 siRNA- and Hey2 vector plasmid-transfected human umbilical vein endothelial cells (HUVECs) resembling EndoMT were monitored by qPCR, immunocytochemistry and western blots. Subsequently, in mice, a Cre-LoxP strategy for inactivation of Hey2 specifically in the endothelium was used to study the biological consequences. Total body irradiation and radiation proctitis were monitored to investigate the impact of conditional Hey2 deletion on intestinal stem cells and microvascular compartment radiosensitivity, EndoMT and rectal damage severity. We found that EndoMT occurs in irradiated HUVECs with concomitant Hey2 mRNA and protein increase. While Hey2 silencing has no effect on radiation-induced EndoMT in vitro, Hey2 overexpression is sufficient to induce phenotypic conversion of endothelial cells. In mice, the conditional deletion of Hey2 reduces EndoMT frequency and the severity of rectal tissue damage. Our data indicate that the reduction in mucosal damage occurs through decline in stem/clonogenic epithelial cell loss mediated by microvascular protection. EndoMT is involved in radiation proctitis and this study demonstrates that a strategy based on the reduction of EndoMT mitigates intestinal tissue damage.
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spelling pubmed-55039942017-07-12 Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice Mintet, Elodie Lavigne, Jérémy Paget, Vincent Tarlet, Georges Buard, Valérie Guipaud, Olivier Sabourin, Jean-Christophe Iruela-Arispe, Maria-Luisa Milliat, Fabien François, Agnès Sci Rep Article The current study evaluated the role of Hey2 transcription factor in radiation-induced endothelial-to-mesenchymal transition (EndoMT) and its impact on radiation-induced tissue damage in mice. Phenotypic modifications of irradiated, Hey2 siRNA- and Hey2 vector plasmid-transfected human umbilical vein endothelial cells (HUVECs) resembling EndoMT were monitored by qPCR, immunocytochemistry and western blots. Subsequently, in mice, a Cre-LoxP strategy for inactivation of Hey2 specifically in the endothelium was used to study the biological consequences. Total body irradiation and radiation proctitis were monitored to investigate the impact of conditional Hey2 deletion on intestinal stem cells and microvascular compartment radiosensitivity, EndoMT and rectal damage severity. We found that EndoMT occurs in irradiated HUVECs with concomitant Hey2 mRNA and protein increase. While Hey2 silencing has no effect on radiation-induced EndoMT in vitro, Hey2 overexpression is sufficient to induce phenotypic conversion of endothelial cells. In mice, the conditional deletion of Hey2 reduces EndoMT frequency and the severity of rectal tissue damage. Our data indicate that the reduction in mucosal damage occurs through decline in stem/clonogenic epithelial cell loss mediated by microvascular protection. EndoMT is involved in radiation proctitis and this study demonstrates that a strategy based on the reduction of EndoMT mitigates intestinal tissue damage. Nature Publishing Group UK 2017-07-10 /pmc/articles/PMC5503994/ /pubmed/28694461 http://dx.doi.org/10.1038/s41598-017-05389-8 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mintet, Elodie
Lavigne, Jérémy
Paget, Vincent
Tarlet, Georges
Buard, Valérie
Guipaud, Olivier
Sabourin, Jean-Christophe
Iruela-Arispe, Maria-Luisa
Milliat, Fabien
François, Agnès
Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
title Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
title_full Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
title_fullStr Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
title_full_unstemmed Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
title_short Endothelial Hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
title_sort endothelial hey2 deletion reduces endothelial-to-mesenchymal transition and mitigates radiation proctitis in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503994/
https://www.ncbi.nlm.nih.gov/pubmed/28694461
http://dx.doi.org/10.1038/s41598-017-05389-8
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