Damage recognition by intestinal stem cells via Draper promotes adult Drosophila midgut regeneration

Tissue regeneration after injury is crucial for restoring epithelial structure and function. Upon damage, a regenerative microenvironment forms that provides signalling cues that stimulate stem cell proliferation to replace lost cells. While this process is well understood, how stem cells themselves sense damage, translate this input into their proliferation and shape the regenerative microenvironment remains unclear. Here we show that Draper-Src-Shark signalling in Drosophila intestinal stem cells (ISCs) recognises tissue damage by sensing externalised phosphatidylserine on dying midgut epithelial cells and is required for STAT activation in ISCs to promote their proliferation. Unlike its role in phagocytosis, Draper in ISCs does not promote the clearance of these apoptotic enterocytes but rather facilitates ISC proliferation in the presence of damaged enterocytes. Moreover, Draper-Src-Shark signalling in progenitors regulates STAT transcriptional activity in the adjacent visceral muscle, indicating that progenitors can shape the regenerative microenvironment beyond tissue boundaries. As Src and STAT are also activated in the mammalian intestinal epithelium after damage and tumour formation, these findings may help develop therapies for tissue regeneration, inflammatory diseases and cancer.