Definition of human intestinal mesenchymal origins and of mesenchymal epithelial cross-talk in health and disease

人类肠道间充质起源以及健康和疾病中间充质上皮串扰的定义

• 批准号: MR/S036377/1
• 负责人: Alison Simmons
• 金额: $ 36.1万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS036377%2F1
• 关键词: Definition; human; intestinal; mesenchymal; origins

Cells such as fibroblasts and smooth muscle cells provide critical structural support in organs such as the gut. Over the last 10 years it has become apparent that these cells play important and diverse cellular functions during embryonic development and in the steady state adult intestine. In addition to their structural roles these cells send signals that control the level of immune cell activity. They also signal to the cells lining the surface of the gut, epithelial cells, to ensure they grow to provide a healthy barrier between the intestinal tissue and the gut microbes. We previously used new state of the art single cell technologies (single-cell RNA-sequencing) to measure genes expressed within single mesenchymal cells isolated from human or mouse colonic mesenchyme in health or during colitis. This revealed the surprising observation of several new cell types within what was previously thought to be one population. We went onto explore these new mesenchymal cell states and demonstrated differing functions and anatomical location within the colonic tissue. The study enabled us to identify which cells in the mesenchyme act as a niche for intestinal epithelial stem cells producing factors required for their differentiation and formation of the epithelial barrier layer of the colon. In colitis we identified important changes in single mesenchymal cells including in emergence of a highly activated population that expressed factors that attract immune cells and factors that impair epithelial function. Abnormal expansion of these disease-associated cells contributes to inflammation observed in diseases such as inflammatory bowel disease. These structural cells also play important roles in intestinal fibrosis, when they produce too much matrix protein that makes tissues stiff and leads to strictures in the intestine that prevent the passage of food and require surgery. Furthermore they play important roles in cancer, fuelling invasiveness and metastatic behaviour in colon cancer. Despite their newly identified and important roles in colon physiology and disease little is known of how these cells arise either in human development or adult state. Little is known about how these cells differentiate into different types and how they control anatomical location of different epithelial cells such as stem cells lining the gut. It is important to identify mesenchymal precursor cells and define the molecular determinants that control emergence of pathogenic populations to revert their aberrant behaviour in disease. Furthermore better understanding of mesenchymal progenitors would enable development of organ-on a chip systems to model human intestine during drug development and enable regenerative medicine approaches for gastrointestinal disease. In this work we will use both single-cell RNA-sequencing and spatial imaging to map human foetal development of colonic mesenchymal cells and the associated colonic epithelial layer with a view to defining a mesenchymal progenitor cell and the molecular cross-talk between mesenchymal and epithelia that dictates formation of healthy barrier. We will use the same approach to define how this relationship breaks down to drive pathology in IBD and colorectal cancer. We will use the foetal development data to inform a search for the colonic mesenchymal stem cell in adult tissue and define functionally if such a cell type exists. This work is critical for advancement of treatments targeting the barrier in both developmental and adult colonic diseases.

成纤维细胞和平滑肌细胞等细胞为肠道等器官提供关键的结构支持。在过去的十年中，这些细胞在胚胎发育和稳定状态的成年肠中发挥着重要的和多样化的细胞功能。除了它们的结构作用外，这些细胞还发送控制免疫细胞活性水平的信号。它们还向肠道表面的上皮细胞发出信号，以确保它们的生长，为肠道组织和肠道微生物之间提供健康的屏障。我们以前使用最先进的单细胞技术（单细胞rna测序）来测量健康或结肠炎期间从人类或小鼠结肠间质分离的单个间质细胞内表达的基因。这揭示了在以前被认为是一个种群的情况下，对几种新细胞类型的惊人观察。我们继续探索这些新的间充质细胞状态，并展示了它们在结肠组织中的不同功能和解剖位置。该研究使我们能够确定间充质中的哪些细胞作为肠上皮干细胞的生态位，产生肠上皮干细胞分化和形成结肠上皮屏障层所需的因子。在结肠炎中，我们发现单个间充质细胞发生了重要变化，包括出现了表达吸引免疫细胞的因子和损害上皮功能的因子的高度活化的细胞群。这些疾病相关细胞的异常扩张有助于炎症性肠病等疾病的炎症。这些结构细胞在肠纤维化中也起着重要作用，当它们产生过多的基质蛋白时，会使组织僵硬，导致肠道狭窄，阻止食物通过，需要手术。此外，它们在癌症中发挥重要作用，促进结肠癌的侵袭和转移行为。尽管它们在结肠生理和疾病中有重要的作用，但人们对这些细胞在人类发育或成人状态下是如何产生的知之甚少。对于这些细胞如何分化成不同类型，以及它们如何控制不同上皮细胞（如肠道内的干细胞）的解剖位置，人们知之甚少。鉴定间充质前体细胞和确定控制致病群体出现的分子决定因素以恢复其在疾病中的异常行为是很重要的。此外，更好地了解间充质祖细胞将有助于在药物开发过程中开发器官芯片系统来模拟人类肠道，并使胃肠道疾病的再生医学方法成为可能。在这项工作中，我们将使用单细胞rna测序和空间成像来绘制人类胎儿结肠间充质细胞和相关结肠上皮层的发育图，以期定义间充质祖细胞以及决定健康屏障形成的间充质和上皮之间的分子交叉对话。我们将使用相同的方法来定义这种关系是如何打破的，从而驱动IBD和结直肠癌的病理。我们将利用胎儿发育数据来寻找成体组织中的结肠间充质干细胞，并从功能上确定这种细胞类型是否存在。这项工作对于推进针对发育和成人结肠疾病屏障的治疗至关重要。

项目成果

Baseline Expression of Immune Gene Modules in Blood is Associated With Primary Response to Anti-TNF Therapy in Crohn's Disease Patients.

血液中免疫基因模块的基线表达与克罗恩病患者对抗 TNF 治疗的主要反应相关。

• DOI: 10.1093/ecco-jcc/jjad166
• 发表时间: 2024
• 期刊: Journal of Crohn's & colitis
• 作者: Bai BYH

A Pilot Study on Automatic Three-Dimensional Quantification of Barrett's Esophagus for Risk Stratification and Therapy Monitoring

• DOI: 10.1053/j.gastro.2021.05.059
• 发表时间: 2021-08-18
• 期刊: GASTROENTEROLOGY
• 影响因子: 29.4
• 作者: Ali, Sharib;Bailey, Adam;Braden, Barbara
• 通讯作者: Braden, Barbara

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis.

上皮细胞上的 HLA-DP 可导致溃疡性结肠炎中 NKp44 自然杀伤细胞造成组织损伤。

• DOI: 10.1053/j.gastro.2023.06.034
• 发表时间: 2023
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Baumdick,MartinE;Niehrs,Annika;Degenhardt,Frauke;Schwerk,Maria;Hinrichs,Ole;Jordan-Paiz,Ana;Padoan,Benedetta;Wegner,LucyHM;Schloer,Sebastian;Zecher,BrittaF;Malsy,Jakob;Joshi,VinitaR;Illig,Christin;Schröder-Schwarz,Jennifer

Dual RNA sequencing reveals dendritic cell reprogramming in response to typhoidal Salmonella invasion.

• DOI: 10.1038/s42003-022-03038-z
• 发表时间: 2022-02-04
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Aulicino A;Antanaviciute A;Frost J;Sousa Geros A;Mellado E;Attar M;Jagielowicz M;Hublitz P;Sinz J;Preciado-Llanes L;Napolitani G;Bowden R;Koohy H;Drakesmith H;Simmons A
• 通讯作者: Simmons A

Cannabis, Cannabinoids, and the Endocannabinoid System-Is there Therapeutic Potential for Inflammatory Bowel Disease?

• DOI: 10.1093/ecco-jcc/jjy185
• 发表时间: 2019-03-30
• 期刊: Journal of Crohn's & colitis
• 作者: Ambrose T;Simmons A
• 通讯作者: Simmons A