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

肠道内排列着一层上皮细胞，确保营养的吸收。为了克服肠道环境的累积损害，这些细胞在我们的一生中迅速得到补充。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节的特定区域：生态位。在过去的十年中，我们对肠道干细胞生态位组织的了解有了显著的进展，主要是对调节干细胞干性的可溶性效应物的表征。然而，关于肠道干细胞生态位组织的几个问题仍未解决。例如：干细胞是如何固定在腺体底部的？调节生态位中不同类型干细胞之间的稳态的机制是什么？

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.