Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA, USA.
Tulane Aging Center, Tulane University School of Medicine, New Orleans, LA, USA.
EMBO J. 2022 Oct 4;41(19):e110834. doi: 10.15252/embj.2022110834. Epub 2022 Aug 11.
Many adult tissues and organs including the intestine rely on resident stem cells to maintain homeostasis and regeneration. In mammals, the progenies of intestinal stem cells (ISCs) can dedifferentiate to generate ISCs upon ablation of resident stem cells. However, whether and how mature tissue cells generate ISCs under physiological conditions remains unknown. Here, we show that infection of the Drosophila melanogaster intestine with pathogenic bacteria induces entry of enteroblasts (EBs), which are ISC progenies, into the mitotic cycle through upregulation of epidermal growth factor receptor (EGFR)-Ras signaling. We also show that ectopic activation of EGFR-Ras signaling in EBs is sufficient to drive enteroblast mitosis cell autonomously. Furthermore, we find that the dividing enteroblasts do not gain ISC identity as a prerequisite to divide, and the regenerative ISCs are produced through EB mitosis. Taken together, our work uncovers a new role for EGFR-Ras signaling in driving EB mitosis and replenishing the ISC pool during fly intestinal regeneration, which may have important implications for tissue homeostasis and tumorigenesis in vertebrates.
许多成年组织和器官，包括肠道，依赖于驻留干细胞来维持体内平衡和再生。在哺乳动物中，肠道干细胞（ISCs）的后代可以在驻留干细胞被清除时去分化为 ISCs。然而，在生理条件下，成熟组织细胞是否以及如何产生 ISCs 仍然未知。在这里，我们表明，感染黑腹果蝇肠道的致病菌通过上调表皮生长因子受体（EGFR）-Ras 信号，诱导 ISC 前体细胞肠母细胞（EBs）进入有丝分裂周期。我们还表明，在 EBs 中外源激活 EGFR-Ras 信号足以驱动肠母细胞自主有丝分裂。此外，我们发现分裂的肠母细胞在分裂之前不会获得 ISC 特性，并且再生的 ISC 是通过 EB 有丝分裂产生的。总之，我们的工作揭示了 EGFR-Ras 信号在驱动 EB 有丝分裂和补充果蝇肠道再生过程中 ISC 池中的新作用，这可能对脊椎动物组织内稳态和肿瘤发生具有重要意义。
