Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 42, Pages E9832-E9841Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1807522115
Keywords
intestinal epithelial cell migration; cytoskeleton remodeling; DNA damage; senescence; SASP
Categories
Funding
- NASA [NNX13AD58G, NNX15AI21G]
- NIH/National Cancer Institute (NCI) [P30-CA051008]
- NATIONAL CANCER INSTITUTE [P30CA051008] Funding Source: NIH RePORTER
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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 gamma-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 Fe-56 radiation relative to control and gamma-rays. Wnt/beta-catenin and its downstream EphrinB/EphB signaling are key to intestinal epithelial cell (IEC) proliferation and positioning during migration, and both are upregulated after Fe-56 radiation. Conversely, factors involved in cell polarity and adhesion and cell-extracellular matrix interactions were persistently down-regulated after Fe-56 irradiation-potentially altering cytoskeletal remodeling and cell extrusion. Fe-56 radiation triggered a time-dependent increase in gamma H2AX 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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