Transcriptome of the Murine Duodenum during Recovery after a Lethal Dose of Total Body Irradiation

Background: In the aftermath of September 11 attacks, the radiobiology community sought novel radiation mitigators capable of preventing death when administered 24 hours or later after exposure to lethal ionizing radiation. The survival and expansion of normal stem cells are crucial for restoring tissue integrity in time to prevent mortality. While U.S. Food and Drug Administration- approved drugs for acute radiation syndrome primarily target the hematopoietic system, restoring the integrity of the intestinal lining is equally important for survival. However, the radiation response of the intestinal stem cell (ISC) population and its niche environment is not as well understood as that of the bone marrow. The aim of this study is to explore early transcriptomic changes in the small intestine after a lethal dose of total body irradiation (TBI) and during subsequent recovery.Materials and Methods: C3H/Sed/Kam mice were irradiated with a TBI dose of 16 Gy, the published 70% lethal dose within 10 days. The compound 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) was administered 24 hours post-irradiation. RNAs from the proximal duodenum were extracted at 28, 72, and 96 hours post-irradiation and subjected to RNA-sequencing. Differentially expressed genes were analyzed using gene-set enrichment analysis.Results and Discussion: Radiation induced significant transcriptomic changes known to precede the death of lymphatic endothelial and epithelial cells. Upregulation of Lgr5+ ISC gene signature was observed during recovery. NSPP treatment further amplified the activation of ISCassociated genes and other regenerative markers. Notably, gene Psrc1 showed strong activation throughout the recovery process, highlighting its potential role in this regenerative response.Conclusion: Our findings highlight potential additional intervention points for mitigating radiation- induced damage in the intestines beyond solely targeting programmed cell death. These insights may contribute to the development of more effective radioprotective approaches, ultimately improving clinical outcomes for individuals undergoing radiotherapy or exposed to high-dose radiation.