GSE174297
In vitro grown organoids treated with IFN? mimicking in vivo intestinal crypts cells aging
Aging-related intestinal dysfunctions include loss of barrier integrity, altered stress responses, nutrient malabsorption, and cancer formation. Influence of aging on intestinal stem cell (ISC) and their niches can explain underlying causes for perturbation in ISC function during aging. However, molecular mechanisms for such decrease in functionality of ISCs during aging remain largely undetermined. Using different transcriptome-wide approaches including single-cell RNA-seq from intestinal crypt cells and immune cells of lamina propria, we characterized age-specific transcriptional programs in the intestinal epithelium. We found that aged ISCs strongly upregulate antigen presenting pathway genes and over-express secretory lineage marker genes leading to a compromised homeostasis of the intestinal epithelium. Mechanistically, increase of interferon gamma (IFNgamma) release by cytotoxic CD4 T cells and innate lymphoid type 2 cells (ILC2) in lamina propria of aged intestine lead to induction of Stat1 in ISCs that trigger MHC class II expression and prime them towards a secretory fate. Altogether these findings, clarify the cross talk between immune cells and ISC in aged intestine and identified the IFNgamma-Stat1-MHCII axis as the key gene network driving intestinal inflammaging phenotype and loss of tissue homeostasis. Our data provide basic and complementary knowledge for the development of therapeutic intervention for aging-related intestinal dysfunction and diseases. Overall design: Single cell RNA sequencing on organoids cultured from isolated crypts of small intestine with control group and treated with IFN?.