Injury-stimulated and self-restrained BMP signaling dynamically regulates stem cell pool size during Drosophila midgut regeneration

Significance Adult stem cells maintain tissue integrity by producing new cells to replenish damaged cells during tissue homeostasis and in response to injury. Using Drosophila adult midgut as a model we show that midgut injury elicited by chemical feeding or bacterial infection stimulates the production of two bone morphogenetic protein (BMP) ligands (Dpp and Gbb) that are critical for the expansion of the intestinal stem cell (ISC) population and midgut regeneration. Interestingly, we find that BMP expression is inhibited by BMP signaling itself, and this autoinhibition is required for resetting ISC pool size to the homeostatic level after tissue repair. Our study suggests that transient expansion of the stem cell population through the dynamic regulation of niche signals serves as a strategy for regeneration. Many adult organs rely on resident stem cells to maintain homeostasis. Upon injury, stem cells increase proliferation, followed by lineage differentiation to replenish damaged cells. Whether stem cells also change division mode to transiently increase their population size as part of a regenerative program and, if so, what the underlying mechanism is have remained largely unexplored. Here we show that injury stimulates the production of two bone morphogenetic protein (BMP) ligands, Dpp and Gbb, which drive an expansion of intestinal stem cells (ISCs) by promoting their symmetric self-renewing division in Drosophila adult midgut. We find that BMP production in enterocytes is inhibited by BMP signaling itself, and that BMP autoinhibition is required for resetting ISC pool size to the homeostatic level after tissue repair. Our study suggests that dynamic BMP signaling controls ISC population size during midgut regeneration and reveals mechanisms that precisely control stem cell number in response to tissue needs.