Transcriptional effects of VIP on murine intestinal stem cells

In our study, we investigated the effect of Vasoactive intestinal peptide (VIP) on murine intestinal stem cell (ISC) activity and differentiation in homeostatic conditions and following irradiation-induced injury. We utilized a model of murine intestinal organoids and observed that VIP promotes epithelial differentiation towards a secretory phenotype predominantly via the p38 MAPK pathway. Moreover, VIP prominently modulates epithelial proliferation as well as the number and proliferative activity of Lgr5-EGFP+ ISC under homeostatic conditions. Further analysis revealed that in vitro acute irradiation injury renders Lgr5-EGFP+ ISC even more susceptible to modulations by VIP, which results in the strong promotion of epithelial regeneration by VIP. Finally, these effects by VIP translate into an in vivo model of abdominal irradiation, where VIP was shown to prominently mitigate radiation-induced injury. Taken together, our findings indicate a prominent role of VIP in modulating ISC behavior in intestinal homeostasis and its potential to promote intestinal regeneration following acute irradiation injury. Overall design: Bulk gene expression data are presented for whole VIP-treated (n=4) or untreated (n=3) organoids, for sorted Lgr5-EGFP+ cells from VIP-treated (n=4) or untreated (n=4) organoids and for sorted Lgr5-EGFP+ cells from VIP-treated (n=4) or untreated (n=4) organoids exposed to irradiation.