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.

在放射性或核事故中，高剂量电离辐射（IR）可能会导致胃肠道综合症（GIS），这是一种急需有效治疗的致命疾病。不幸的是，当前基于天然产物和抗氧化剂的治疗在缓解致命的GIS方面显示出非常有限的作用。储备肠道干细胞（ISC）和分泌祖细胞都可以补充受损细胞，并有助于隐窝再生。然而，在这些缓慢循环的细胞中，β-catenin/ c-MYC轴受到抑制，导致致命的意外伤害期间，恢复肠道完整性的再生反应有限。当前的研究表明，IRGAR TIGAR是小鼠肠道内c-MYC的关键下游靶标，IR后的过表达在Bmi1-creERT ^+中引起增生性反应保留ISC，从而使小鼠免于致命的IR暴露。至关重要的是，通过消除有害的活性氧（ROS）但保留了增殖的ROS信号，TIGAR过表达增强了激活蛋白1的活性，这对于致命辐射后启动储备ISC分裂是必不可少的。此外，识别出TIGAR感应只齿轮的LGR5 ^-亚群储备ISC的的再生隐窝和肠TIGAR过表达显示相当于肠重建到储备-ISC-限制TIGAR诱导。我们的发现表明，对Lgr5进行精确管理^- 储备ISC是解决不可预知的致命伤害的有前途的策略，TIGAR可以用作意外辐射诱发GIS的治疗目标。