Neuroendocrine Control of Intestinal Regeneration Through the Vascular Niche in Drosophila.

Robust and controlled intestinal regeneration is essential for the preservation of organismal health and wellbeing and involves reciprocal interactions between the intestinal epithelium and its microenvironment. While knowledge of regulatory roles of the microenvironment on the intestine is vast, how distinct perturbations within the intestinal epithelium may influence tailored responses from the microenvironment, remains understudied. Here, we present previously unknown signaling between enteroendocrine cells (EE), vasculature-like trachea (TTCs), and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Injury-induced ROS from midgut epithelial cells promotes the production and secretion of Dh31, the homolog of mammalian Calcitonin Gene-Related Peptide (CGRP), from anterior midgut EE cells. Dh31 from EE cells and neurons signal to Dh31 receptor within TTCs leading to cell autonomous production of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF)-like Pvf1. Tracheal derived Pvf1 induces remodeling of the tracheal stem cell niche and regenerative ISC proliferation through autocrine and paracrine Pvr/MAPK signalling, respectively. Interestingly, while EE Dh31 exerts broad control of ISC proliferation throughout the midgut, functions of the neuronal source of the ligand appear restricted to the posterior midgut. Altogether, our work has led to the discovery of a novel enteroendocrine/neuronal/vascular signaling network controlling global and domain specific ISC proliferation during adult intestinal regeneration.