Single-cell RNA Sequencing Reveals How the Aryl Hydrocarbon Receptor Shapes Cellular Differentiation Potency in the Mouse Colon.
Single-cell RNA Sequencing Reveals How the Aryl Hydrocarbon Receptor Shapes Cellular Differentiation Potency in the Mouse Colon.
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DOI：
10.1158/1940-6207.capr-21-0378
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Chapkin RS
中科院分区：
文献类型：
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作者：
Yang Y;Osorio D;Davidson LA;Han H;Mullens DA;Jayaraman A;Safe S;Ivanov I;Cai JJ;Chapkin RS
尽管最近的进展认识到芳香烃受体（Ahr）依赖的信号转导在抑制结肠肿瘤发生的重要性，其在调节结肠隐窝内稳态的作用仍然不清楚。为了评估Ahr对肠上皮细胞异质性和功能表型的影响，我们利用单细胞转录组学和先进的分析策略，从野生型和结肠特异性Ahr敲除小鼠中生成结肠肠隐窝的高质量图谱。在此，我们观察了Ahr缺失对隐窝相关典型上皮细胞类型和杯状细胞亚型以及深隐窝分泌细胞中FOXM 1调控基因的促进作用。我们还表明，肠Ahr缺失提高单细胞熵（分化能力或细胞干细胞的措施）和RNA速度长度（细胞分化率的措施）在非循环和循环LGR 5+干细胞。在一般情况下，通过可溶性和膜结合因子的细胞间信号串扰在Ahr空结肠细胞扰动。总之，我们的单细胞RNA测序分析提供了Ahr在体内调节假定的干细胞驱动基因、细胞潜能谱系决定和细胞-细胞通信中的分子功能的新证据。
Despite recent progress recognizing the importance of aryl hydrocarbon receptor (Ahr)-dependent signaling in suppressing colon tumorigenesis, its role in regulating colonic crypt homeostasis remains unclear. To assess the effects of Ahr on intestinal epithelial cell heterogeneity and functional phenotypes, we utilized single-cell transcriptomics and advanced analytical strategies to generate a high-quality atlas for colonic intestinal crypts from wild-type and intestinal-specific Ahr knockout mice. Here we observed the promotive effects of Ahr deletion on FOXM1 regulated genes in crypt-associated canonical epithelial cell types and subtypes of goblet cells and deep crypt secretory cells. We also show that intestinal Ahr deletion elevated single-cell entropy (a measure of differentiation potency or cell stemness) and RNA velocity length (a measure of the rate of cell differentiation) in noncycling and cycling Lgr5+ stem cells. In general, intercellular signaling crosstalk via soluble and membrane-bound factors was perturbed in Ahr null colonocytes. Taken together, our single-cell RNA sequencing analyses provide new evidence of the molecular function of Ahr in modulating putative stem cell driver genes, cell potency lineage decisions and cell-cell communication in vivo.