Inter-organ regulation ofDrosophilaintestinal stem cell proliferation by a hybrid organ boundary zone

SUMMARY STATEMENT Gene expression at the Drosophila midgut-hindgut boundary is a hybrid of both organs. Hybrid cells repress stem cell division, but boundary injury activates stem cell division through inter-organ JAK-STAT signaling. ABSTRACT The molecular identities and regulation of cells at inter-organ boundaries are often unclear, despite the increasingly appreciated role of organ boundaries in disease. Using Drosophila as a model, here we show that a specific population of adult midgut organ boundary intestinal stem cells (OB-ISCs) is regulated by the neighboring hindgut, a developmentally distinct organ. This distinct OB-ISCs control is due to proximity to a specialized transition zone between the endodermal midgut and ectodermal hindgut that shares molecular signatures of both organs, which we term the hybrid zone (HZ). During homeostasis, proximity to the HZ restrains OB-ISC proliferation. However, injury to the adult HZ/hindgut drives up-regulation of upaired-3 cytokine and OB-ISC hyperplasia. If HZ disruption is severe, hyperplastic OB-ISCs expand across the inter-organ boundary. Our data suggest that inter-organ signaling plays an important role in controlling OB-ISCs in homeostasis and injury repair, which is likely critical in prevention of disease.