Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117, Hungary.
Cornell Institute of Host-Microbe Interactions and Disease, Department of Entomology, Cornell University, Ithaca, New York, United States of America.
Sci Rep. 2018 Mar 15;8(1):4644. doi: 10.1038/s41598-018-23065-3.
Intestinal homeostasis is maintained by tightly controlled proliferation and differentiation of tissue-resident multipotent stem cells during aging and regeneration, which ensures organismal adaptation. Here we show that autophagy is required in Drosophila intestinal stem cells to sustain proliferation, and preserves the stem cell pool. Autophagy-deficient stem cells show elevated DNA damage and cell cycle arrest during aging, and are frequently eliminated via JNK-mediated apoptosis. Interestingly, loss of Chk2, a DNA damage-activated kinase that arrests the cell cycle and promotes DNA repair and apoptosis, leads to uncontrolled proliferation of intestinal stem cells regardless of their autophagy status. Chk2 accumulates in the nuclei of autophagy-deficient stem cells, raising the possibility that its activation may contribute to the effects of autophagy inhibition in intestinal stem cells. Our study reveals the crucial role of autophagy in preserving proper stem cell function for the continuous renewal of the intestinal epithelium in Drosophila.
肠道内稳态通过组织驻留多能干细胞在衰老和再生过程中的增殖和分化来维持，这确保了机体的适应性。在这里，我们表明自噬在果蝇肠道干细胞中是必需的，以维持增殖，并保持干细胞池。自噬缺陷的干细胞在衰老过程中表现出更高的 DNA 损伤和细胞周期停滞，并通过 JNK 介导的细胞凋亡频繁消除。有趣的是，DNA 损伤激活激酶 Chk2 的缺失会导致细胞周期停滞，并促进 DNA 修复和细胞凋亡，从而导致肠道干细胞的不受控制的增殖，而与自噬状态无关。Chk2 在自噬缺陷的干细胞核内积累，这增加了其激活可能有助于自噬抑制对肠道干细胞的影响的可能性。我们的研究揭示了自噬在维持果蝇肠道上皮细胞的连续更新过程中适当的干细胞功能方面的关键作用。
