Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.
Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.
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DOI：
10.1016/j.cell.2018.08.067
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发表时间：
2018-10-04
期刊：
影响因子：
64.5
通讯作者：
Simmons A
中科院分区：
文献类型：
--
作者：
Kinchen J;Chen HH;Parikh K;Antanaviciute A;Jagielowicz M;Fawkner-Corbett D;Ashley N;Cubitt L;Mellado-Gomez E;Attar M;Sharma E;Wills Q;Bowden R;Richter FC;Ahern D;Puri KD;Henault J;Gervais F;Koohy H;Simmons A
肠间充质细胞在上皮细胞稳态、基质重塑、免疫和炎症中发挥重要作用。但在这些过程中，结肠间质的异质性程度仍然未知。使用超过16，500个结肠间充质细胞的无偏单细胞分析，我们揭示了除了周细胞和肌成纤维细胞外，表达不同转录调节因子和功能通路的成纤维细胞的四个子集。我们确定了一个位于上皮隐窝附近的小生境人口表达SOX 6，F3（CD 142），和WNT基因结肠上皮干细胞功能所必需的。在结肠炎中，我们观察到这种生态位的失调和活化的间充质细胞群的出现。该亚群表达TNF超家族成员14（TNFSF 14）、成纤维网状细胞相关基因、IL-33和赖氨酰氧化酶。此外，它还诱导了损害上皮细胞增殖和成熟的因子，并导致体内氧化应激和疾病严重程度。我们的工作定义了IBD中结肠间充质重塑如何促进炎症和屏障功能障碍。结肠间充质的单细胞普查揭示了意想不到的异质性表达SOX 6和Wnt的结肠隐窝龛间充质细胞的鉴定结肠炎相关间充质细胞的分析揭示了致病性驱动因素人类结肠间充质细胞的单细胞谱鉴定了表达导致上皮细胞功能障碍和炎症的因子的结肠炎相关群体。
Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts. We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD. Single-cell census of the colonic mesenchyme reveals unexpected heterogeneity Identification of the colonic crypt niche mesenchymal cell expressing SOX6 and Wnts Definition of fundamental aspects of mesenchymal remodeling in colitis Analysis of colitis-associated mesenchymal cells reveals pathogenicity drivers Single-cell profiling of human colonic mesenchymal cells identifies a colitis-associated population that expresses factors contributing to epithelial cell dysfunction and inflammation.
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