Inter-organ regulation of Drosophila intestinal stem cell proliferation by a hybrid organ boundary zone

Abstract

The molecular identities and regulation of cells at interorgan boundaries are often unclear, despite the increasingly appreciated role of organ boundaries in disease. Using as a model, we here 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-ISC control occurs through 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 upregulation of cytokine, which signals through a Signal transducer and activator of transcription (STAT) protein to promote cell division only in OB-ISCs. If HZ disruption is severe, hyperplastic OB-ISCs expand across the interorgan boundary. Our data suggest that interorgan signaling plays an important role in controlling OB-ISCs in homeostasis and injury repair, which is likely to be crucial in prevention of disease.

An abundant quiescent stem cell population inDrosophilaMalpighian tubules protects principal cells from kidney stones

“…Other regions of the gut are maintained and repaired in different ways. The hindgut lacks specialized stem cells and following damage is maintained primarily by induced polyploidization of post-mitotic epithelial cells (Cohen et al, 2018;Fox and Spradling, 2009;Losick et al, 2013;Sawyer et al, 2017).…”

Accelerated cell cycles enable organ regeneration under developmental time constraints in theDrosophilahindgut

“…To distinguish between these two models, we acutely injured the larval hindgut and assessed whole-animal development progression (Methods). For tissue injury, we used the temporally and spatially regulated Gal4-UAS expression system, driven by a hindgut-specific enhancer of the brachyenteron (byn) gene to induce the apoptotic genes head involution defective (hid) and reaper (rpr) (Cohen et al, 2018;Fox and Spradling, 2009;Losick et al, 2013;Sawyer et al, 2017;Smith-Bolton et al, 2009). We induced injury at either the 2 nd or early 3 rd larval instar (L2-L3) stages or at the wandering third instar (hereafter L3W) stage.…”

“…We assayed cell death, cell number, and the frequency of pyloric cells with the mitotic marker Phospho-Histone H3 (PH3, Methods) during We next identified the number of additional mitotic cell cycles that the L3W pylorus must undergo following injury to produce the expanded adult pylorus and also the adult ileum. In the absence of injury, our previous lineage tracing experiments identified that L3W pyloric cells destined to produce the adult pylorus undergo approximately 2-3 divisions (yielding 5-6 cell clones in adults), whereas pyloric cells destined to generate the adult ileum undergo one division to make up the adult ileum (yielding 2 cell clones in adults) (Cohen et al, 2018;Fox and Spradling, 2009;Sawyer et al, 2017). In the presence of injury, our lineage tracing following L3W injury indicated a 3-fold increase in recovered adult pyloric clone size (from 5-6 cells to ~16 cells) and a doubling of ileal clone size (from 2 cells to 4 cells, Cohen et al, 2018).…”

“…As documented by Robertson over 80 years ago (Robertson, 1936), the larval ileum undergoes histolysis, and is replaced by regenerative activity from adult hindgut precursors. Cell division from the larval pylorus, which occurs during metamorphosis, is the source of the expanded adult pylorus, and also the new adult ileum (Cohen et al, 2020;Fox and Spradling, 2009;Sawyer et al, 2017;Takashima et al, 2008;Yang and Deng, 2018). This development is not disrupted by a severe, acute injury to the wandering 3 rd instar larval pylorus.…”

“…Unlike the larval pylorus, injury to the adult pylorus results in endocycles, a cell cycle in which cells replicate DNA without mitosis, leading to polyploidization and hypertrophy (Cohen et al, 2018;Fox and Duronio, 2013;Fox and Spradling, 2009;Losick et al, 2013;Sawyer et al, 2017).…”