Stem cell-specific depletion of NF-kB transcription factor Relish alters intestinal response to DSS induced injury

Immune pathways are important regulators of intestinal stem cell function, yet how these pathways act within stem cells in not well known. To determine the function of immunity in stem cells of the intestine we used Drosophila as a model. We knocked down the NF-kB family transcription factor Relish in intestinal stem cells and upon exposure to the colitis inducing chemical DSS, these intestines become hyperplastic and the flies die faster. We then performed single cell RNA sequencing to determine the role of Relish in stem cells upon damage. With the sequencing data we found profound effects of Relish depletion on the ability of the intestine to produce premature enterocytes upon damage. Within stem cells, Relish altered the expression of EGF/Ras regulators. Further experiments showed that Relish acts through Ras in stem cells to control intestinal cell death and proliferation to modulate repair upon injury. Given the important role immunity and Ras signaling plays in intestinal homeostasis and disease our findings uncover important insight into the mechanisms in which immune pathways control stem cell function and intestinal health.