Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki 00790, Finland.
Institute of Biotechnology, University of Helsinki, Helsinki 00790, Finland.
Sci Adv. 2024 Feb 9;10(6):eadi2671. doi: 10.1126/sciadv.adi2671.
The adult intestine is a regionalized organ, whose size and cellular composition are adjusted in response to nutrient status. This involves dynamic regulation of intestinal stem cell (ISC) proliferation and differentiation. How nutrient signaling controls cell fate decisions to drive regional changes in cell-type composition remains unclear. Here, we show that intestinal nutrient adaptation involves region-specific control of cell size, cell number, and differentiation. We uncovered that activation of mTOR complex 1 (mTORC1) increases ISC size in a region-specific manner. mTORC1 activity promotes Delta expression to direct cell fate toward the absorptive enteroblast lineage while inhibiting secretory enteroendocrine cell differentiation. In aged flies, the ISC mTORC1 signaling is deregulated, being constitutively high and unresponsive to diet, which can be mitigated through lifelong intermittent fasting. In conclusion, mTORC1 signaling contributes to the ISC fate decision, enabling regional control of intestinal cell differentiation in response to nutrition.
成年肠道是一个区域化的器官，其大小和细胞组成根据营养状况进行调整。这涉及到肠道干细胞（ISC）增殖和分化的动态调节。然而，营养信号如何控制细胞命运决定，以驱动细胞类型组成的区域变化仍不清楚。在这里，我们表明肠道营养适应涉及细胞大小、细胞数量和分化的区域特异性控制。我们发现，mTOR 复合物 1（mTORC1）的激活以区域特异性的方式增加 ISC 的大小。mTORC1 活性促进 Delta 的表达，将细胞命运导向吸收性肠母细胞谱系，同时抑制分泌性肠内分泌细胞分化。在老年果蝇中，ISC mTORC1 信号通路失调，持续处于高水平且对饮食无反应，这可以通过终身间歇性禁食来缓解。总之，mTORC1 信号通路有助于 ISC 命运决定，从而能够根据营养状况实现肠道细胞分化的区域控制。
