Damage recognition by intestinal stem cells via Draper-Src-Shark-STAT signalling promotes adult Drosophila midgut regeneration

Regeneration after injury is crucial for maintaining epithelial structure and function. In order to facilitate this, a regenerative niche forms upon damage that produces cues to induce stem cell proliferation to replace damaged or lost cells. Whereas much is known about this process, less is understood about how stem cells themselves sense damage, translate this into their proliferation and shape the regenerative niche. In the adult Drosophila midgut, the non-receptor tyrosine kinase Src42A is required in progenitors to promote ISC proliferation after pathogenic bacterial infection. Although STAT is necessary for Src42A-driven ISC proliferation, the mechanism by which Src42A activates STAT in progenitors remains unclear. Here we show that Draper-Src-Shark signalling acts in ISCs to recognise midgut damage and is required for full STAT activation in ISCs to promote their proliferation. Unlike its role in phagocytes, we find that the engulfment receptor Draper in ISCs does not promote the engulfment of dying midgut epithelial cells but rather is required for ISC proliferation only in the presence of apoptotic enterocytes. Moreover, we uncover that Draper-Src-Shark signalling in progenitors regulates STAT activity non-cell autonomously in the visceral muscle, indicating that progenitors can shape the regenerative niche. As both Src and Stat are activated in the mammalian intestinal epithelium after damage and tumour formation, our work likely extends to mammalian organisms and may aid in developing therapies for tissue regeneration, inflammatory diseases and cancer.