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

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？是什么机制调节了生态位中存在的不同类型干细胞之间的动态平衡？ 基于我们在过去20年中对肠道细胞受体及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，利用我们实验室开发的人肠上皮隐窝细胞系(HIEC)及其最近的衍生品，包括HIEC干细胞，我们现在可以直接解决这些问题。 因此，在这个研究项目中，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，我们提出了三个目标，描述短期、中期和长期方法，以证明细胞-母体相互作用调节干细胞分离和锚定并直接调节基因表达。 我们前两个目标的发现将代表支持细胞-母体相互作用调节肠道干细胞功能的概念证明。预计我们在第三个长期目标中的发现将成为新假说的基础，这些假说将进一步促进我们对调节和调节肠道以及其他器官中干细胞生态位的机制的理解。

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 three aims describing short, middle and long term approaches to demonstrate that cell-matrisome interactions mediate stem cell segregation and anchoring and directly regulate gene expression. The findings from our first two aims will represent the proof of concept in support of cell-matrisome interactions regulating intestinal stem cell function. It is expected that our findings in the third long term aim will form the basis of new hypotheses that will further advance our comprehension of the mechanisms that modulate and regulate the stem cell niche in the intestine and, likely, in other organs.