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Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine

Proliferative gastrointestinal (GI) tissue is radiation-sensitive, and heavy-ion space radiation with its high-linear energy transfer (high-LET) and higher damaging potential than low-LET γ-rays is predicted to compromise astronauts’ GI function. However, much uncertainty remains in our understandin...

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Autores principales: Kumar, Santosh, Suman, Shubhankar, Fornace, Albert J., Datta, Kamal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196540/
https://www.ncbi.nlm.nih.gov/pubmed/30275302
http://dx.doi.org/10.1073/pnas.1807522115
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author Kumar, Santosh
Suman, Shubhankar
Fornace, Albert J.
Datta, Kamal
author_facet Kumar, Santosh
Suman, Shubhankar
Fornace, Albert J.
Datta, Kamal
author_sort Kumar, Santosh
collection PubMed
description Proliferative gastrointestinal (GI) tissue is radiation-sensitive, and heavy-ion space radiation with its high-linear energy transfer (high-LET) and higher damaging potential than low-LET γ-rays is predicted to compromise astronauts’ GI function. However, much uncertainty remains in our understanding of how heavy ions affect coordinated epithelial cell migration and extrusion, which are essential for GI homeostasis. Here we show using mouse small intestine as a model and BrdU pulse labeling that cell migration along the crypt–villus axis is persistently decreased after a low dose of heavy-ion (56)Fe radiation relative to control and γ-rays. Wnt/β-catenin and its downstream EphrinB/EphB signaling are key to intestinal epithelial cell (IEC) proliferation and positioning during migration, and both are up-regulated after (56)Fe radiation. Conversely, factors involved in cell polarity and adhesion and cell–extracellular matrix interactions were persistently down-regulated after (56)Fe irradiation—potentially altering cytoskeletal remodeling and cell extrusion. (56)Fe radiation triggered a time-dependent increase in γH2AX foci and senescent cells but without a noticeable increase in apoptosis. Some senescent cells acquired the senescence-associated secretory phenotype, and this was accompanied by increased IEC proliferation, implying a role for progrowth inflammatory factors. Collectively, this study demonstrates a unique phenomenon of heavy-ion radiation-induced persistently delayed IEC migration involving chronic sublethal genotoxic and oncogenic stress-induced altered cytoskeletal dynamics, which were seen even a year later. When considered along with changes in barrier function and nutrient absorption factors as well as increased intestinal tumorigenesis, our in vivo data raise a serious concern for long-duration deep-space manned missions.
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spelling pubmed-61965402018-10-23 Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine Kumar, Santosh Suman, Shubhankar Fornace, Albert J. Datta, Kamal Proc Natl Acad Sci U S A PNAS Plus Proliferative gastrointestinal (GI) tissue is radiation-sensitive, and heavy-ion space radiation with its high-linear energy transfer (high-LET) and higher damaging potential than low-LET γ-rays is predicted to compromise astronauts’ GI function. However, much uncertainty remains in our understanding of how heavy ions affect coordinated epithelial cell migration and extrusion, which are essential for GI homeostasis. Here we show using mouse small intestine as a model and BrdU pulse labeling that cell migration along the crypt–villus axis is persistently decreased after a low dose of heavy-ion (56)Fe radiation relative to control and γ-rays. Wnt/β-catenin and its downstream EphrinB/EphB signaling are key to intestinal epithelial cell (IEC) proliferation and positioning during migration, and both are up-regulated after (56)Fe radiation. Conversely, factors involved in cell polarity and adhesion and cell–extracellular matrix interactions were persistently down-regulated after (56)Fe irradiation—potentially altering cytoskeletal remodeling and cell extrusion. (56)Fe radiation triggered a time-dependent increase in γH2AX foci and senescent cells but without a noticeable increase in apoptosis. Some senescent cells acquired the senescence-associated secretory phenotype, and this was accompanied by increased IEC proliferation, implying a role for progrowth inflammatory factors. Collectively, this study demonstrates a unique phenomenon of heavy-ion radiation-induced persistently delayed IEC migration involving chronic sublethal genotoxic and oncogenic stress-induced altered cytoskeletal dynamics, which were seen even a year later. When considered along with changes in barrier function and nutrient absorption factors as well as increased intestinal tumorigenesis, our in vivo data raise a serious concern for long-duration deep-space manned missions. National Academy of Sciences 2018-10-16 2018-10-01 /pmc/articles/PMC6196540/ /pubmed/30275302 http://dx.doi.org/10.1073/pnas.1807522115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Kumar, Santosh
Suman, Shubhankar
Fornace, Albert J.
Datta, Kamal
Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
title Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
title_full Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
title_fullStr Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
title_full_unstemmed Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
title_short Space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
title_sort space radiation triggers persistent stress response, increases senescent signaling, and decreases cell migration in mouse intestine
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196540/
https://www.ncbi.nlm.nih.gov/pubmed/30275302
http://dx.doi.org/10.1073/pnas.1807522115
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