Stem cell-derived signals in intestinal stem cell homeostasis: investigating the role of SPARC, PLOD, dlp and Timp in the Drosophila midgut

Abstract

Epithelia are constantly turned over as cells are lost from the surface of the tissue and replaced by the proliferation of stem cells. Epithelial stem cells must be tightly regulated to maintain homeostasis and prevent over-proliferation of the tissue, which can lead to hyperplasia and play important roles in disease development and progression. The intestinal stem cells of the Drosophila midgut are an ideal model system to identify regulators of intestinal stem fate, and study their function and regulation. We have identified several candidate regulators of Drosophila intestinal stem cells that are heavily involved in various aspects of extracellular matrix organization: PLOD, SPARC, dlp and TIMP. The aim of this project is to explore their effects on intestinal stem cell proliferation and on the maintenance of gut homeostasis, using a wide range of genetic manipulation techniques available in the fly. Results suggest that all four proteins play varying roles in the regulation and proliferation of intestinal stem cells in the posterior midgut, which is regulated by a wide range of signalling pathways, including Ras/MAPK, Notch, JNK and Hippo signaling. All 4 proteins are highly conserved in metazoans, and their misregulation has been implicated in disease development, raising the possibility of a conserved role in regulating intestinal stem cells in higher organisms. In vitro analyses of human prostate cancer samples were carried out in order to determine if the findings from the Drosophila model system were conserved in human tissues, and explore their translation applications as potential therapeutic targets.