Pvf1-PvR-mediated crosstalk between the trachea and the gut guides intestinal stem cell migration to promote gut regeneration.

Abstract

In adult tissues, stem cells (SCs) reside in specialized niches, where they are maintained in a quiescent state until activated by injury. Once activated, they migrate towards injured sites, where they proliferate and differentiate to replenish lost or damaged cells. Although effective tissue repair relies critically on the ability of SCs to reach and populate damaged sites, mechanisms guiding SCs towards these sites are not well understood. This is largely due to the technical challenges involved in monitoring SC dynamics in real time in vivo. Here, we devised an experimental framework that allows for real-time tracking of the spatiotemporal dynamics of intestinal SCs (ISCs) during the early phases of gut regeneration. Our data show that ISC migration is rapidly induced following injury and precedes ISC divisions and differentiation. We identify the Drosophila PDGF-VEGF-related receptor, Pvr, as a critical regulator of the migratory response to epithelial damage. ISC-specific Pvr depletion strongly suppresses ISC migration towards affected sites as well as the regenerative response. We further show that the Pvr ligand, PDGF-VEGF-related factor 1 (Pvf1), is produced by the trachea/vasculature in response to intestinal damage and acts as a guidance signal to direct ISC migration towards affected areas. Our work highlights a critical role of gut-trachea/vasculature crosstalk in guiding ISC migration during regeneration. As neovascularization of injured sites is a key feature of tissue repair in both flies and mammals, these findings could be relevant to regenerative processes in a wide range of adult tissues.