Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

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.