Abstract
During radiologic or nuclear accidents, high-dose ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a deadly disorder that urgently needs effective therapy. Unfortunately, current treatments based on natural products and antioxidants have shown very limited effects in alleviating deadly GIS. Reserve intestinal stem cells (ISCs) and secretory progenitor cells are both reported to replenish damaged cells and contribute to crypt regeneration. However, the suppressed β-catenin/c-MYC axis within these slow-cycling cells leads to limited regenerative response to restore intestinal integrity during fatal accidental injury. Current study demonstrates that post-IR overexpression of TIGAR, a critical downstream target of c-MYC in mouse intestine, mounts a hyperplastic response in Bmi1-creERT+ reserve ISCs, and thus rescues mice from lethal IR exposure. Critically, by eliminating damaging reactive oxygen species (ROS) yet retaining the proliferative ROS signals, TIGAR-overexpression enhances the activity of activator protein 1, which is indispensable for initiating reserve-ISC division after lethal radiation. In addition, it is identified that TIGAR-induction exclusively gears the Lgr5− subpopulation of reserve ISCs to regenerate crypts, and intestinal TIGAR-overexpression displays equivalent intestinal reconstruction to reserve-ISC-restricted TIGAR-induction. Our findings imply that precise administrations toward Lgr5− reserve ISCs are promising strategies for unpredictable lethal injury, and TIGAR can be employed as a therapeutic target for unexpected radiation-induced GIS.
Highlights
Unexpected radiation exposure during terrorist events, industrial or nuclear accidents is a current and continuing threat to the future
Given that both of the reserve intestinal stem cells (ISCs) and Lgr5+ label-retaining secretory progenitor cells contribute to intestinal regeneration, mice containing the loxp-stop-loxp-Tigar cassette allele were crossed with Bmi1-creERT mice and Lgr5-EGFP-IRES
Using cultured mouse miniguts in vitro, i.e., epithelial organoids that preserved the in vivo celltype distribution and kinetics of intestinal crypts and villi[21,22], it was found that around 24.6 ± 3.05% of organoids derived from Bmi1-creERT;H11-Tigar mice were robustly labeled with GFP at 7 days after 12-Gy irradiation (Fig. 1k, l)
Summary
Unexpected radiation exposure during terrorist events (e.g., the use of “dirty bombs”), industrial or nuclear accidents (such as the nuclear disasters in Chernobyl and Fukushima) is a current and continuing threat to the future. Besides the high-proliferating and radiosensitive Lgr5high ISCs (i.e., crypt base columnar cells (CBCs)), a slow-cycling and injury-resistant pool of stem cells could be arisen to divide when the CBCs are depleted[9,10]. These rare “+4” position cells mainly include the reserve ISCs marked by lineage tracing analysis with polycomb complex protein 1 (Bmi1)-creERT11,12 and Lgr5+ label-retaining secretory progenitor cells which are regarded functionally distinct from reserve ISCs13,14. During lethal IR exposure, the CBCs are exhausted rapidly and the intestinal epithelium always disintegrates around 5 days after radiation, which happens even prior to effective “+4”-position-cell division and crypt regeneration.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
