Asano Jumpei, Sato Taku, Ichinose Shizuko, Kajita Mihoko, Onai Nobuyuki, Shimizu Shigeomi, Ohteki Toshiaki
Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Saitama 332-0012, Japan.
Cell Rep. 2017 Aug 1;20(5):1050-1060. doi: 10.1016/j.celrep.2017.07.019.
Autophagy is a lysosomal degradation pathway with important roles in physiological homeostasis and disease. However, the role of autophagy in intestinal stem cells (ISCs) is unclear. Here, we show that intrinsic autophagy in ISCs is important for ISC homeostasis. Mice lacking autophagy protein 5 (ATG5) in intestinal epithelial cells (iECs) (Villin-Cre: Atg5, hereafter Atg5 mice) or in all iECs except Paneth cells (Ah-Cre: Atg5 mice) had significantly fewer ISCs than did control mice and showed impaired ISC-dependent intestinal recovery after irradiation. Crypt ISCs from Atg5 mice had significantly higher reactive oxygen species (ROS) levels than did those from control mice. A ROS-inducing reagent decreased the ISC number and impaired ISC regenerative capacity ex vivo, and treating Atg5 mice with an antioxidant rescued their defects. Our results show that intrinsic autophagy supports ISC maintenance by reducing excessive ROS. Optimizing autophagy may lead to autophagy-based therapies for intestinal injuries.
自噬是一种溶酶体降解途径，在生理稳态和疾病中发挥着重要作用。然而，自噬在肠干细胞（ISC）中的作用尚不清楚。在此，我们表明ISC中的内在自噬对ISC稳态至关重要。在肠上皮细胞（iEC）中缺乏自噬蛋白5（ATG5）的小鼠（Villin-Cre:Atg5，以下简称Atg5小鼠）或除潘氏细胞外所有iEC中缺乏ATG5的小鼠（Ah-Cre:Atg5小鼠）的ISC数量明显少于对照小鼠，并且在照射后显示出依赖于ISC的肠道恢复受损。Atg5小鼠的隐窝ISC的活性氧（ROS）水平明显高于对照小鼠。一种ROS诱导试剂在体外减少了ISC数量并损害了ISC的再生能力，用抗氧化剂治疗Atg5小鼠可挽救其缺陷。我们的结果表明，内在自噬通过减少过量的ROS来支持ISC的维持。优化自噬可能会导致基于自噬的肠道损伤治疗方法。
