新型间质细胞亚群在肠道区域免疫中的功能及调控机制

The gut is not only the largest digestive organ but also an organ with greatly enriched immune cells and tissues. Its unique microenvironment and diverse cell types all contribute to the gut immune homeostasis. Perturbation of this homeostasis will lead to various intestinal and systematic diseases including inflammatory bowel diseases (IBD), cancer, and metabolic syndromes. The underlying cellular and molecular mechanisms that govern the homeostasis of the gut immunity remain to be the major challenge of immunology field. In this proposal, we will focus on the recently be attracted and relatively under-studied intestinal cell subtypes, namely the intestinal stromal cells, for their function and mechanisms in gut immunity. With the combination of single cell RNA sequencing and genetic mouse models, we have generated exciting preliminary data that reveal novel sub-groups of stromal cells in the inflamed gut producing RSPO1 regulated by the ROS-MEKK2-MAPK pathway, which facilitates intestinal epithelial recovery and ameliorates IBD progression. We have also realized that these subsets of the stromal cells have potential abilities to produce cytokines for activating macrophages, innate lymphoid cells and B cells, all of which are essential cell types for gut immune homeostasis. We will continue to systematically profile the sub-populations of the stromal cells for their ontogeny, proliferation, and functions, especially the cross regulation of these subset of cells with other immune cells under health and disease conditions by applying single cell sequencing, FACSymphony, FateID, CyTOF, multicolor confocal as well as in vivo live imaging techniques, combined with patient derived organoid and mouse genetics studies. We believe that the studies from this proposal will shed new light for our deep understanding of gut immunity and may provide new intervention targets or strategies for the treatment of inflammatory bowel diseases and perhaps other gut associated diseases.

肠道是人体重要的区域免疫器官，肠道多种细胞类型及肠道微环境构成肠道免疫微生态场，维持免疫稳态，稳态失衡导致炎性肠病（IBD）等肠道疾病乃至全身性疾病。肠道免疫稳态的形成机制目前仍不甚清楚。本项目聚焦近年来受到重点关注但所知尚少的间质细胞及其亚群在肠道免疫中的细胞和分子机制，深入剖析肠道区域免疫特性和稳态维持机理。我们前期研究揭示间质细胞存在全新亚群，IBD条件下间质细胞亚群受MEKK2通路调控分泌RSPO1促进上皮修复与肠炎缓解。单细胞测序结果显示这些亚群还具有调控巨噬细胞、固有淋巴细胞及B细胞的潜在能力，在本项目中我们将整合运用单细胞测序、在体显微成像和多色流式等技术，结合基因敲除小鼠和IBD病人样本，阐明间质细胞亚群增殖、起源及其调控效应免疫细胞的方式，揭示肠道微环境调控这些亚群的新型级联信号，为全面理解肠道区域免疫的调控机制提供新视角，为IBD等相关疾病的治疗提供新靶点和新策略。

肠道是人体重要的区域免疫器官，本项目聚焦近年来新发现的肠道间质细胞及其亚群在肠道免疫稳态维持中的细胞和分子机制。我们通过单细胞测序、显微成像以及多色流式等技术，结合IBD病人样本和基因敲除小鼠模型，并利用间质细胞的培养体系，部分阐明了间质细胞新亚群在肠道免疫稳态维持和IBD发生中的具体功能以及作用机制。同时，利用单细胞转录组测序手段对比分析了小鼠和人肠道间质细胞亚群，建立了IBD病人组织间质细胞单细胞图谱，找到了潜在的促进损伤修复的对应亚群。另外，通过这些单细胞数据，我们还发现了肠道和结直肠癌内的固有淋巴细胞ILCs亚群的分布特征及肿瘤内间质细胞-巨噬细胞相互作用形成肿瘤边界的分子机制。这些研究将带来对肠道区域免疫特性的全新认知，加深对IBD、肠癌发生发展机制的理解，从而为研发治疗IBD、肠癌等疾病提供新的靶点和策略。