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Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9832-E9841. doi: 10.1073/pnas.1807522115. Epub 2018 Oct 1.

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

Author information

1
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057.
2
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.
3
Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC 20057; kd257@georgetown.edu.

Abstract

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 56Fe 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 56Fe radiation. Conversely, factors involved in cell polarity and adhesion and cell-extracellular matrix interactions were persistently down-regulated after 56Fe irradiation-potentially altering cytoskeletal remodeling and cell extrusion. 56Fe 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.

KEYWORDS:

DNA damage; SASP; cytoskeleton remodeling; intestinal epithelial cell migration; senescence

PMID:
30275302
PMCID:
PMC6196540
DOI:
10.1073/pnas.1807522115
[Indexed for MEDLINE]
Free PMC Article

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