Institute of Radiation Medicine, Fudan University, Shanghai, 200032, China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Suzhou, 215123, China.
Cell Death Dis. 2020 Jul 6;11(7):501. doi: 10.1038/s41419-020-2715-6.
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) 可导致胃肠道综合征 (GIS)，这是一种急需有效治疗的致命疾病。不幸的是，基于天然产物和抗氧化剂的当前治疗方法在缓解致命 GIS 方面显示出非常有限的效果。储备肠干细胞 (ISCs) 和分泌祖细胞都被报道可以补充受损细胞并有助于隐窝再生。然而，这些缓慢循环细胞内受抑制的 β-连环蛋白/c-MYC 轴导致对致命意外损伤时恢复肠道完整性的有限再生反应。本研究表明，IR 后 TIGAR 的过度表达，即 c-MYC 在小鼠肠道中的关键下游靶标，可在 Bmi1-creERT 储备 ISCs 中引发增生反应，从而使小鼠免受致命 IR 暴露的影响。至关重要的是，通过消除有害的活性氧 (ROS) 而保留增殖性 ROS 信号，TIGAR 过表达增强了激活蛋白 1 的活性，这对于致命辐射后储备 ISC 分裂的起始是必不可少的。此外，研究确定 TIGAR 诱导仅使储备 ISCs 的 Lgr5 亚群能够再生隐窝，并且肠道 TIGAR 过表达显示出与储备 ISC 限制的 TIGAR 诱导相当的肠道重建。我们的研究结果表明，针对 Lgr5 储备 ISCs 的精确给药是应对不可预测的致命损伤的有前途的策略，并且 TIGAR 可以作为意外辐射诱导的 GIS 的治疗靶点。
