The Drosophila midgut: a model for stem cell driven tissue regeneration

Abstract

The Drosophila and mammalian digestive systems bear striking similarities in genetic control and cellular composition, and the Drosophila midgut has emerged as an amenable model for dissecting the mechanisms of tissue homeostasis. The Drosophila midgut is maintained by multipotent intestinal stem cells (ISCs) that give rise to all cell types in the intestinal epithelium and are required for long-term tissue homeostasis. ISC proliferation rate increases in response to a myriad of chemical and bacterial insults through the release of JAK-STAT and EGFR ligands from dying enterocytes that activate the JAK-STAT and EGFR pathways in ISCs. The Hippo and JNK pathways converge upon JAK-STAT and EGFR signaling, presumably in response to specific stresses, and JNK and insulin signaling have been shown to be critical in response to age-related stresses. This review details these emerging mechanisms of tissue homeostasis and the proliferative response of ISCs to epithelial damage, environmental stresses, and aging.

FIGURE 1

Intestinal stem cells (ISCs) are multipotent and give rise to all cell types in the intestinal epithelium. (a) ISCs divide asymmetrically to self-renew and give rise to an enteroblast (EB) daughter cell. The EB goes on to differentiate into either an enterocyte (EC) or enteroendocrince (ee) cell, depending on the level of N signaling in the EB. (b) ISCs are located along the basement membrane and the EB daughter moves away from the basement membrane upon division. The underlying visceral muscle contacts the entire epithelium.

FIGURE 2

Enterocyte (EC) damage elicits a proliferative response in intestinal stem cells (ISCs). Upon EC damage, Unpaired (Upd) and Epidermal Growth Factor Receptor (EGFR) ligands are released and initiate the Janus Kinas-Signal Transducer and Activator of Transcription (JAK-STAT) and EGFR pathways, respectively, in the ISC which induced ISC proliferation. Both the Jun N-terminal kinase (JNK) and Hippo (Hpo) pathways feed into JAK-STAT and EGFR signaling though the activation or inhibition of Yorkie (Yki), respectively.