Nutrient-driven dedifferentiation of enteroendocrine cells promotes adaptive intestinal growth
Nutrient-driven dedifferentiation of enteroendocrine cells promotes adaptive intestinal growth
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DOI：
10.1101/2023.05.08.539820
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发表时间：
2023-05
期刊：
影响因子：
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通讯作者：
Hiroki Nagai;L. A. E. Nagai;Sohei Tasaki;Ryuichiro Nakato;Daiki Umetsu;E. Kuranaga;M. Miura;
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文献类型：
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作者：
Hiroki Nagai;L. A. E. Nagai;Sohei Tasaki;Ryuichiro Nakato;Daiki Umetsu;E. Kuranaga;M. Miura;
发育后的器官再生在不断变化的营养环境下提高了生物体的适应性。虽然干细胞丰度是适应性细胞增殖的基本决定因素，但我们对其潜在机制的理解仍然主要限于干细胞分裂的调节。在这里，我们表明，营养波动诱导果蝇成年中肠去分化，驱动适应性肠道生长。从谱系追踪和单细胞RNA测序，我们确定了一个肠内分泌细胞（EE）的亚群，通过激活JAK-STAT途径转化为功能性肠干细胞（ISCs），以响应饮食中的葡萄糖和氨基酸。EE衍生的ISC的基因消融严重损害ISC扩增和中肠生长，尽管保留了驻留的ISC，并且计算机模拟进一步表明EE去分化能够有效增加中肠细胞数量，同时维持上皮细胞组成。我们的研究结果揭示了一种生理诱导的去分化，它确保了ISC在适应性器官生长过程中与营养条件相一致的扩张。
Post-developmental organ resizing improves organismal fitness under constantly changing nutrient environments. Although stem cell abundance is a fundamental determinant of adaptive resizing, our understanding of its underlying mechanisms remains primarily limited to the regulation of stem cell division. Here we demonstrate that nutrient fluctuation induces dedifferentiation in the Drosophila adult midgut to drive adaptive intestinal growth. From lineage tracing and single-cell RNA-sequencing, we identify a subpopulation of enteroendocrine cells (EEs) that convert into functional intestinal stem cells (ISCs) in response to dietary glucose and amino acids by activating the JAK-STAT pathway. Genetic ablation of EE-derived ISCs severely impairs ISC expansion and midgut growth despite the retention of resident ISCs, and in silico modeling further indicates that EE dedifferentiation enables efficient increase in the midgut cell number while maintaining epithelial cell composition. Our findings uncover a physiologically-induced dedifferentiation that ensures ISC expansion during adaptive organ growth in concert with nutrient conditions.