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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 42; pp. E9832 - E9841
• Main Authors: Kumar, Santosh, Suman, Shubhankar, Fornace, Albert J., Datta, Kamal
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 16.10.2018
• Series: PNAS Plus
• Subjects: Animals; Apoptosis; Astronauts; Biological Sciences; Cell adhesion & migration; Cell growth; Cell migration; Cell Movement - radiation effects; Cellular Senescence - radiation effects; Cellular stress response; Cytoskeleton; Digestive system; Energy transfer; Epithelial cells; Epithelial Cells - radiation effects; Extracellular matrix; Extraterrestrial radiation; Extrusion; Gamma Rays - adverse effects; Genotoxicity; Heavy ions; Homeostasis; Inflammation; Intestines - pathology; Intestines - radiation effects; Iron isotopes; Iron Radioisotopes - adverse effects; Irradiation; Linear energy transfer (LET); Male; Mice; Mice, Inbred C57BL; Phenotypes; PNAS Plus; Polarity; Radiation; Radiation damage; Radiation dosage; Radiation effects; Senescence; Signal Transduction - radiation effects; Signaling; Small intestine; Space missions; Stress, Physiological - radiation effects; Time dependence; Tumorigenesis; Villus; Whole-Body Irradiation - adverse effects; Wnt protein; β-Catenin; senescence; intestinal epithelial cell migration; cytoskeleton remodeling; SASP; DNA damage
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1807522115

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 upregulated 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.