Department of Electrical & Computer Engineering, Texas A&M University, College Station, Texas.
Department of Veterinary Integrative Biosciences, Texas A&M University College of Veterinary Medicine and Biomedical Sciences, College Station, Texas.
Cancer Prev Res (Phila). 2022 Jan;15(1):17-28. doi: 10.1158/1940-6207.CAPR-21-0378. Epub 2021 Nov 22.
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 analytic 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 -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 stem cells. In general, intercellular signaling cross-talk 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 . PREVENTION RELEVANCE: Our mouse single-cell RNA sequencing analyses provide new evidence of the molecular function of Ahr in modulating colonic stemness and cell-cell communication . From a cancer prevention perspective, Ahr should be considered a therapeutic target to recalibrate remodeling of the intestinal stem cell niche.
尽管最近在认识芳基烃受体 (Ahr)-依赖性信号在抑制结肠肿瘤发生中的重要性方面取得了进展，但它在调节结肠隐窝稳态中的作用仍不清楚。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，为野生型和肠道特异性 Ahr 敲除小鼠的结肠肠隐窝生成了高质量的图谱。在这里，我们观察到 Ahr 缺失对隐窝相关典型上皮细胞类型和杯状细胞和深隐窝分泌细胞亚型中 - 调节基因的促进作用。我们还表明，肠道 Ahr 缺失增加了非循环和循环 - 干细胞中单细胞熵（分化潜力或细胞干性的度量）和 RNA 速度长度（细胞分化率的度量）。一般来说，通过可溶性和膜结合因子的细胞间信号转导在 Ahr 缺失的结肠细胞中受到干扰。总之，我们的单细胞 RNA 测序分析为 Ahr 调节潜在干细胞驱动基因、细胞潜能谱系决定和细胞间通讯的分子功能提供了新的证据。预防相关性：我们的小鼠单细胞 RNA 测序分析为 Ahr 调节结肠干性和细胞间通讯的分子功能提供了新的证据。从癌症预防的角度来看，Ahr 应该被视为一种治疗靶点，以重新调整肠道干细胞龛的重塑。
