System Biology Lecture Series - Nir Yosef: Exploring T– epithelial interactions in the inflamed gut

Nir Yosef / Weizmann Institute of Science, Rehovot, Israel

Abstract: Chronic inflammation in the intestine disrupts the integrity of the epithelial monolayer that forms the barrier between the host and the luminal environment and impairs its renewal through differentiation of stem cells. While the importance of T helper cells in the related human diseases and mouse models is established, less is known about how these cells influence the gut epithelium and particularly its stem cell compartment during inflammation. In this talk I will present our efforts in that area, using single cell RNA-seq and spatial transcriptomis in several mouse models of intestinal inflammation. We mapped the cellular architecture of the inflamed colon at crypt-scale resolution, establishing several inflammation-induced populations of intestinal stem cells and their progeny. Using new approaches for spatial co-localization analysis, we identified and experimentally tested several modes of inflammation-associated interactions between T cells, intestinal stem cells, and their epithelial progeny, mediated through both cytokine signaling and metabolite exchange. Collectively, these findings point to a spatial code in which the positioning of immune cells relative to intestinal stem cells is an important determinant of mucosal inflammation. Interwoven throughout the talk, I will also describe computational tools that we have developed to enable more powerful analysis of spatial transcriptomics, ranging from normalization issues to approaches for inferring how cells interact with their surroundings.