Evidence that inflammation-associated fibroblasts (IAFs) originate from Edil3 stromal "mesitocytes" in the colon following radiation injury

Stromal cells present in the colon crypt provide proliferation and differentiation signals to the epithelial cells, thereby maintaining their integrity and stimulating the regeneration process. Cancer patients treated for tumors located in the abdominopelvic region may develop radiation proctitis, a condition characterized by a strong mucosal inflammation. In this work, single-cell RNA sequencing approaches were combined with spatial transcriptomics to characterize colonic stromal cells in depth, both in control conditions and in the context of radiation-induced ulceration. The present study identifies a novel stromal marker, Edil3 (EGF-like repeats and discoidin domains 3), which defines the major stromal population of the colon. This population is spatially and functionally distinct from telocytes and trophocytes and is expressed along the crypt with a functional proliferation-differentiation axis . This population, which we propose to name "mesitocytes," cooperates with vascular cells to control inflammation and epithelial proliferation. We demonstrate that radiation-induced ulcerated areas are characterized by the presence of inflammation-associated fibroblasts (IAFs) deriving from mesitocytes. scRNA-seq datas of Stroma cells from Colon from Male C57BL/6JRj control mice (CTR9, n=9) or from colon 2 weeks from irradaiation from mice were exposed to irradiation at 26 GY focus on the colorectal area (IR_W2, n=7). A total of 16 samples is included in this study.

结肠隐窝中的基质细胞可为上皮细胞提供增殖与分化信号，从而维持其结构完整性并刺激再生过程。针对腹盆腔区域肿瘤接受治疗的癌症患者可能罹患放射性直肠炎（radiation proctitis），该病以显著的黏膜炎症为特征。本研究将单细胞RNA测序（single-cell RNA sequencing）与空间转录组学（spatial transcriptomics）相结合，对对照组及辐射诱导溃疡状态下的结肠基质细胞进行了深度表征。本研究鉴定出一种新型基质细胞标志物Edil3（EGF-like repeats and discoidin domains 3），该标志物可定义结肠中的主要基质细胞群。该细胞群在空间分布与功能特性上均区别于Telocytes（Telocytes）与滋养细胞（trophocytes），沿结肠隐窝分布并呈现功能增殖分化轴特征。我们将该细胞群命名为"间质细胞（mesitocytes）"，其可与血管细胞协同调控炎症反应与上皮细胞增殖。本研究证实，辐射诱导的溃疡区域存在由间质细胞分化而来的炎症相关成纤维细胞（inflammation-associated fibroblasts, IAFs）。本研究的单细胞RNA测序（scRNA-seq）数据来源于两类样本：雄性C57BL/6JRj对照小鼠的结肠基质细胞（CTR9，n=9），以及接受26 Gy结直肠区域聚焦辐射、于辐射后2周采集的小鼠结肠样本（IR_W2，n=7）。本研究共纳入16份样本。