Kong Lingjia, Subramanian Sathish, Segerstolpe Åsa, Tran Vy, Shih Angela R, Carter Grace T, Kunitake Hiroko, Twardus Shaina W, Li Jasmine, Gandhi Shivam, Kaper Marco E, Cauley Christy, Chen Eric J, Porter Caroline B M, Delorey Toni M, Bordeianou Liliana, Ricciardi Rocco, Ananthakrishnan Ashwin N, Lau Helena, Graham Daniel B, Hodin Richard, Deguine Jacques, Smillie Christopher S, Xavier Ramnik J
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Nat Genet. 2025 Jun 25. doi: 10.1038/s41588-025-02225-y.
Fibrosis is a major complication of Crohn's disease (CD) marked by excess deposition of extracellular matrix, leading to stricturing and functional impairment. As mechanistic characterization and therapeutic options are lacking, we paired single-cell and spatial transcriptomics in 61 samples from 21 patients with CD and 10 patients without inflammatory bowel disease (IBD). Intestinal strictures were characterized by increased immune cells, including IgG plasma cells, CCR7-hi CD4 T cells and inflammatory fibroblasts. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Furthermore, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.
纤维化是克罗恩病（CD）的主要并发症，其特征是细胞外基质过度沉积，导致狭窄和功能障碍。由于缺乏机制表征和治疗选择，我们对21例CD患者和10例无炎症性肠病（IBD）患者的61个样本进行了单细胞和空间转录组学分析。肠道狭窄的特征是免疫细胞增加，包括IgG浆细胞、CCR7高表达的CD4 T细胞和炎性成纤维细胞。空间转录组学表明，关键亚群在患病组织内共定位，并鉴定出其他细胞群，如 Cajal 间质细胞和肠神经元。此外，我们将基因表达映射到肠道生物地理学上，发现已知的遗传风险位点在由炎性成纤维细胞和淋巴滤泡定义的离散空间模块中富集。总之，我们的数据集描绘了狭窄性CD中的关键转录组和细胞网络，并突出了多细胞遗传风险因素的空间组织。
