Neuroendocrine control of intestinal regeneration through the vascular niche in Drosophila

Robust and controlled intestinal regeneration involves reciprocal interactions between the intestinal epithelium and its microenvironment. Here, we identify signaling between enteroendocrine (EE) cells, vasculature-like trachea, and neurons, which drives regional and global stem cell proliferation during adult intestinal regeneration in Drosophila. Reactive oxygen species (ROS) from midgut cells promote production and secretion of diuretic hormone 31 (Dh31), from anterior midgut EE cells. EE and neuronal Dh31 activate tracheal Dh31 receptor, leading to the production of the vascular endothelial growth factor (VEGF)- and platelet-derived-growth-factor (PDGF)-like ligand Pvf1. Pvf1 induces tracheal remodeling and intestinal stem cell (ISC) proliferation through autocrine and paracrine Pvr/mitogen-activated protein kinase (MAPK) signaling, respectively. While EE Dh31 exerts broad control of ISC proliferation throughout the midgut, effects of the neuronal source of the ligand appear restricted to the posterior midgut. Collectively, our work discovered an EE/neuronal/vascular signaling network, controlling global and domain-specific ISC proliferation during adult intestinal regeneration.