Colonic epithelial cell diversity in health and inflammatory bowel disease
Colonic epithelial cell diversity in health and inflammatory bowel disease
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DOI：
10.1038/s41586-019-0992-y
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发表时间：
2019-03-07
期刊：
影响因子：
64.8
通讯作者：
Simmons, Alison
中科院分区：
文献类型：
--
作者：
Parikh, Kaushal;Antanaviciute, Agne;Simmons, Alison
结肠上皮促进宿主-微生物的相互作用，控制粘膜免疫，协调营养循环，形成粘液屏障。上皮屏障的破坏是炎症性肠病(IBD)的基础。然而，每种上皮细胞亚型在这一过程中的具体作用尚不清楚。在这里，我们描述了来自IBD患者和未受影响的对照组的单个结肠上皮细胞。我们确定了以前未知的细胞亚型，包括肠隐窝内的祖细胞、结肠细胞和杯状细胞的梯度。在隐窝的顶部，我们发现了一个以前未知的吸收细胞，它表达质子通道OTOP2和饱腹肽uroguanylin，它感知pH，并在炎症和癌症中调节失调。在IBD中，我们观察到杯状细胞的位置重塑，这与WFDC2的下调一致-WFDC2是一种我们发现由杯状细胞表达并抑制细菌生长的抗蛋白酶分子。在体内，WFDC2保持了上皮细胞之间紧密连接的完整性，并防止了共生细菌的入侵和粘膜炎症。我们描述了标志物和转录状态，鉴定了结肠上皮细胞，并揭示了IBD屏障破坏的基本决定因素。
The colonic epithelium facilitates host-microorganism interactions to control mucosal immunity, coordinate nutrient recycling and form a mucus barrier. Breakdown of the epithelial barrier underpins inflammatory bowel disease (IBD). However, the specific contributions of each epithelial-cell subtype to this process are unknown. Here we profile single colonic epithelial cells from patients with IBD and unaffected controls. We identify previously unknown cellular subtypes, including gradients of progenitor cells, colonocytes and goblet cells within intestinal crypts. At the top of the crypts, we find a previously unknown absorptive cell, expressing the proton channel OTOP2 and the satiety peptide uroguanylin, that senses pH and is dysregulated in inflammation and cancer. In IBD, we observe a positional remodelling of goblet cells that coincides with downregulation of WFDC2-an antiprotease molecule that we find to be expressed by goblet cells and that inhibits bacterial growth. In vivo, WFDC2 preserves the integrity of tight junctions between epithelial cells and prevents invasion by commensal bacteria and mucosal inflammation. We delineate markers and transcriptional states, identify a colonic epithelial cell and uncover fundamental determinants of barrier breakdown in IBD.