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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-07-10

AUTHORS

Elodie Mintet, Jérémy Lavigne, Vincent Paget, Georges Tarlet, Valérie Buard, Olivier Guipaud, Jean-Christophe Sabourin, Maria-Luisa Iruela-Arispe, Fabien Milliat, Agnès François

ABSTRACT

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. More... »

PAGES

4933

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-05389-8

DOI

http://dx.doi.org/10.1038/s41598-017-05389-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1090523251

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28694461


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32 schema: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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39 EndoMT
40 HEY2 overexpression
41 HUVEC
42 Hey2
43 Hey2 mRNA
44 Western blot
45 biological consequences
46 blot
47 body irradiation
48 cell loss
49 cells
50 conditional deletion
51 consequences
52 conversion
53 current study
54 damage
55 damage severity
56 data
57 decline
58 deletion
59 effect
60 endothelial cells
61 endothelium
62 epithelial cell loss
63 factors
64 frequency
65 immunocytochemistry
66 impact
67 inactivation
68 increase
69 intestinal stem cells
70 intestinal tissue damage
71 irradiation
72 loss
73 mRNA
74 mesenchymal transition
75 mice
76 microvascular protection
77 modification
78 mucosal damage
79 overexpression
80 phenotypic conversion
81 phenotypic modifications
82 proctitis
83 protection
84 protein increases
85 qPCR
86 radiation proctitis
87 radiation-induced tissue damage
88 radiosensitivity
89 reduction
90 resembling
91 role
92 severity
93 siRNA
94 silencing
95 stem cells
96 strategies
97 study
98 tissue damage
99 total body irradiation
100 transcription factors
101 transition
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