Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells
Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells
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DOI：
10.15252/embj.2019104319
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发表时间：
2020-08-10
期刊：
影响因子：
11.4
通讯作者：
Chapkin, Robert S.
中科院分区：
文献类型：
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作者：
Han, Huajun;Davidson, Laurie A.;Chapkin, Robert S.
芳烃受体（AhR）是一种配体激活的转录因子，可以感知外源性物质、饮食和肠道微生物衍生的代谢产物，越来越多地被认为是肠道生物学的关键调节因子。然而，其对结肠干细胞和祖细胞功能的影响在很大程度上仍未被探索。在这里，我们观察到Lgr 5（+）干细胞中AhR的可诱导缺失增加了结肠干细胞的百分比，并增强了类器官启动能力和分选的干细胞和祖细胞的生长，而AhR活化具有相反的效果。此外，在临床前结肠炎相关肿瘤模型中，垂体特异性AhR敲除通过上调FoxM 1信号传导增加基底干细胞和隐窝损伤诱导的细胞增殖并促进结肠肿瘤发生。AhR在转录上抑制FoxM 1的表达。人类类器官中AhR的激活重现了在小鼠中观察到的表型，例如结肠干细胞百分比的降低，干细胞分化的促进和FoxM 1信号传导的减弱。这些发现表明，AhR-FoxM 1轴，至少部分，介导结肠干/祖细胞的行为。
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5(+)stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal-specific AhR knockout increases basal stem cell and crypt injury-induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR-FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.