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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=753459
• 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.

肠道内只有一层上皮细胞，确保营养物质的吸收。为了克服肠道环境的累积损害，这些细胞在我们的一生中会迅速补充。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：壁龛。在过去的十年里，我们对肠道干细胞生态位的组织结构的了解在描述调节茎的可溶性效应方面取得了显着的进展。然而，关于肠道干细胞生态位组织的几个问题仍然悬而未决。例如：干细胞是如何固定在腺体底部的？在过去的二十年里，基于我们对肠道细胞受体与其细胞外基质不溶性配体之间相互作用的研究，我们认为这种特殊的细胞-基质相互作用在肠道干细胞生态位的组织中起着关键作用。传统上，如果没有足够的实验细胞模型，这些问题很难解决。然而，利用我们实验室建立的人肠上皮隐窝细胞系(HIEC)及其最新的衍生物，包括HIEC干细胞样细胞，我们现在可以直接解决这些问题。在本研究计划中，我们建议使用HIEC细胞和HIEC来源的细胞来表征细胞-基质复合体对肠道干细胞生态位的贡献。更具体地说，我们提出了两个目标来描述特定的方法来证明细胞-基底体相互作用介导干细胞动态锚定并直接调节基因表达。我们的第一个目标是确定营养不良多糖对肠道干细胞基因表达锚定和调控的影响，这是支持细胞-基质相互作用调节肠道干细胞功能的概念证明。第二个目标是，我们对细胞-基质相互作用的进一步分子和功能特征的研究结果将形成新的假设基础，以促进我们对肠道和其他器官中干细胞生态位调节和调节机制的理解。