Cell-matrisome interactions as a key component of the intestinal stem cell niche

细胞-基质相互作用是肠道干细胞生态位的关键组成部分

• 批准号: RGPIN-2017-05489
• 负责人: Beaulieu, JeanFrançois
• 金额: $ 2.91万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=644907
• 关键词: Cell; matrisome; interactions; key; component

The intestine is lined with a single layer of epithelial cells that ensure nutrient uptake. To overcome cumulative damages from the intestinal environment, these cells are replenished rapidly throughout our lifetime. A stem cell population, located in the lower region of the glands, is responsible for the continual production of new cells. As in other organs, stem cells in the intestine are confined to a specific region where the microenvironment is tightly regulated: the niche. Our knowledge about the organization of the intestinal stem cell niche has significantly progressed over the last decade for the characterization of the soluble effectors that regulate stemness. However, several questions about intestinal stem cell niche organization remain open. For instance: How do stem cells remain anchored at the base of the glands? What are the mechanisms that regulate the homeostasis between the different types of stem cells present in the niche?******Based on our work on the interactions between intestinal cell receptors and their extracellular matrix insoluble ligands referred to as the "matrisome" over the last two decades, we propose that such specific cell-matrisome interactions play a key role in the organization of the intestinal stem cell niche. These questions have been traditionally difficult to address without adequate experimental cell models. However, using the human intestinal epithelial crypt cell (HIEC) line developed in our laboratory and its recent derivatives including the HIEC stem-like cells, we can now directly address these questions.******In this research program, we are thus proposing to use HIEC cells and HIEC-derived cells to characterize the contribution of the cell-matrisome complex to the intestinal stem cell niche. More specifically, we are proposing two aims describing specific approaches to demonstrate that cell-matrisome interactions mediate stem cell dynamic anchoring and directly regulate gene expression. ******Our first aim, which consists to characterize the effects of dystroglycan on the anchoring and regulation of gene expression of intestinal stem cells, represents the proof of concept in support of cell-matrisome interactions regulating intestinal stem cell function.******In the second aim, our findings on further molecular and functional characterizations of cell-matrisome interactions will form the basis of new hypotheses for advancing our comprehension of the mechanisms that modulate and regulate the stem cell niche in the intestine and, likely, in other organs.***

肠道内衬单层上皮细胞，确保营养吸收。为了克服肠道环境的累积损伤，这些细胞在我们的一生中迅速补充。位于腺体下部的干细胞群负责不断产生新细胞。与其他器官一样，肠道中的干细胞被限制在微环境受到严格调控的特定区域：生态位。在过去的十年里，我们对肠道干细胞生态位组织的了解在表征调节干细胞性的可溶性效应物方面取得了显着进展。然而，关于肠干细胞生态位组织的几个问题仍然是开放的。例如：干细胞如何保持锚定在腺体的底部？什么是调节生态位中不同类型干细胞之间稳态的机制？**基于我们在过去二十年中对肠细胞受体与其细胞外基质不溶性配体（称为“基质体”）之间相互作用的研究，我们提出这种特定的细胞-基质体相互作用在肠干细胞生态位的组织中起着关键作用。这些问题一直难以解决，没有足够的实验细胞模型。然而，使用我们实验室开发的人肠上皮隐窝细胞（HIEC）系及其最近的衍生物，包括HIEC干细胞样细胞，我们现在可以直接解决这些问题。因此，在这项研究计划中，我们建议使用HIEC细胞和HIEC衍生细胞来表征细胞-基质体复合物对肠干细胞生态位的贡献。更具体地说，我们提出了两个目标，描述了具体的方法来证明细胞-基质体相互作用介导干细胞动态锚定和直接调控基因表达。** 我们的第一个目标是表征肌营养不良蛋白聚糖对肠道干细胞基因表达的锚定和调节的影响，代表了支持调节肠道干细胞功能的细胞-基质体相互作用的概念证明。在第二个目标中，我们对细胞-基质体相互作用的进一步分子和功能表征的发现将形成新假设的基础，以促进我们对调节和调节肠道中以及可能的其他器官中的干细胞生态位的机制的理解。