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Intestinal stem cells and tissue regeneration in Drosophila
Humans and fruit flies do not look alike, yet many physiological processes in these two organisms share homologous molecules.We use Drosophila melanogaster, the common fruit fly, as a model organism to study the mechanisms by which intestinal stem cells respond to injury and initiate tissue repair. Around 1% of the US population experience inflammatory diseases of the intestine. Prolonged inflammation and tissue injury has also been proposed to potentiate gastrointestinal (GI) cancer. To understand how cells in the GI tract interact with wide varieties of microbes and pathogenic substances is important for developing therapeutic strategies that alleviate intestinal diseases. The human gastrointestinal tract is the major nutrient absorption organ that also has immune and endocrine function. It is also a major site for interaction with commensal bacteria and pathogenic substances. However, the human gastrointestinal tract is a relatively under-explored organ due to the complexity of the organ and the difficulty in experimental manipulation. Stem cell-mediated tissue repair is a promising approach for intestinal diseases. A major problem in intestinal stem cell research is that specific markers that can unambiguously identify these stem cells remain rare and the functions of these markers remain difficulty to study.
My laboratory focuses on understanding how Drosophila intestinal stem cells mediate repair after tissue damage. Drosophila has emerged as a powerful tool for analyzing the function of human disease genes, either as fly homologues or by expressing in transgenic flies the mutated forms of human genes. Drosophila midgut is only 1 cm long and has a relatively simple cellular organization. Midgut intestinal stem cells have recently been identified that function to replenish the different cell types. We have demonstrated that these Drosophila intestinal stem cells can increase their division rate in response to tissue damage. Using this newly established system, we also show that intestinal stem cell division requires insulin signaling, a mechanism not yet shown in mammals thus suggesting that new information can be obtained from this system. To analyze how insulin and other regulatory pathways control intestinal stem cell division is our ongoing research direction. We have identified by transgenic expression assays and RNAi-based genetic screens a number of genes that are essential for damage-induced intestinal stem cell division. By studying the mechanisms of tissue damage-induced stem division in the genetically amenable Drosophila system, important insights will hopefully be obtained that can help to understand human stem cell-mediated tissue repair, intestinal inflammatory diseases and cancer progression.
Cellular organization in adult Drosophila midgut. Left panel is DAPI staining for DNA in midgut. Right panel is a confocal image of midgut cross section. Phalloidin stains smooth muscle cells at the basal side and brush border of enterocytes at the lumenal side. Intestinal stem cells are some of the small cells located near the basal side. In adult Drosophila midgut, intestinal stem cell is the only cell type that divides and gives rise to all other cell types. We want to understand how the stem cell division is regulated, how the damaged epithelium is repaired, and how differentiation into various cell types is determined.
Project #1: Mechanistic study of isolated mutants that show abnormal intestinal stem cell division phenotypes.
Project #2:Perform transgenic RNAi-based genetic screen for genes required for intestinal stem cell response to tissue damage.
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