Human intestinal organoid models reveal fundamental differences between stem cell and differentiated cells response to enteric pathogens

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Talk abstract:

The intestinal epithelium is a primary barrier separating us from the outside environment. This barrier is formed by a monolayer of cells which is composed of multiple cell types organized along a specific crypt-villi axis. The bottom of the crypt contains the stem cell niche and these cells will differentiate to give rise to all cell lineages found in the human intestinal epithelium: the absorptive enterocytes and the secretory cells (Goblet, Paneth, and enteroendocrine). Using human intestinal organoid model systems, we could show that intestinal epithelial cells can distinguish between enteric challenges emanating from the luminal content of the gut vs challenges emanating the tissue side. This unique polarized response allows epithelial cells to partially tolerate the presence of the commensals while still remaining fully immune responsive against enteric pathogens. Interestingly, using single cell RNA sequencing we could reveal that stem cells displayed a unique basal cell type specific transcriptional landscape of interferon stimulated genes and pro-inflammatory cytokines compared to differentiated cells. Additionally, when infected by enteric viruses, each cell type mounted a unique immune response. Our results suggest that each individual cell type contributes to gut homeostasis by uniquely responding to the enteric pathogens and likely to the commensal bacteria.