Many animal tissues undergo homeostatic growth in which spent differentiated cells are replaced by the progeny of resident stem or progenitor cells. In the epithelial lining of animal intestines high rates of cell turnover are presumed to vary according to changes in food composition and dietary exposures to toxins, pathogens, and chemical or mechanical injury. To maintain normal gut structure and function (i.e.
homeostasis) intestinal stem cells likely respond to variations in cell loss with corresponding changes in rates of self-renewal and differentiation. How this occurs is not well understood. According to a prevalent view of the vertebrate intestine, stem- and transient amplifying cell divisions in the crypts of Lieberkühn, promoted by WNT signaling, drive gut epithelial renewal in a “conveyor-belt” fashion, generating a constant supply of differentiated cells to the villi, where they are autonomously exfoliated (Gregorieff and Clevers, 2005
; Sancho et al., 2004
). In its simplest form this model does not incorporate feedback from the differentiated epithelium to progenitor cells, and therefore lacks the means to maintain stasis when rates of epithelial cell loss vary. More sophisticated models that do incorporate feedback have been discussed: for instance negative cross-talk between BMP signaling in the villi and WNT signaling in the crypts might allow true homeostasis (Crosnier et al., 2006
; Gregorieff and Clevers, 2005
). But rigorous tests of the cross-regulatory interactions required have so far not been possible in a vertebrate. In this respect the Drosophila
midgut, which is simpler than its vertebrate counterparts but has similar cell types and signaling interactions, is technically advantageous.
adult midgut is maintained by intestinal stem cells (ISCs) that self-renew and also produce the two principal differentiated cell types of the intestinal epithelium, absorptive enterocytes (ECs) and secretory enteroendocrine (EE) cells (Micchelli and Perrimon, 2006
; Ohlstein and Spradling, 2006
). The midgut also maintains many non-dividing, undifferentiated ISC daughters termed enteroblasts (EBs), which can differentiate directly. Differentiation requires Delta/Notch signaling from the ISC to its EB daughter and, as in mammals, the fate decision taken (absorptive vs. secretory) is thought to depend upon the intensity of Notch signaling received by an EB (Ohlstein and Spradling, 2007
). Lineage analysis suggests that differentiated cells in the midgut epithelium turn over roughly weekly in well-fed flies, as in mammals.
Studies of dissociated Lepidopteran midguts found that cell death caused by Bacillus thuringiensis (Bt)
endotoxin stimulated the division of a population of cells that were probably ISCs (Hakim et al., 2001
; Loeb et al., 2001
), and recent reports document mitoses in Drosophila
midguts in response to ingested detergent (Amcheslavsky et al., 2009
) or bacteria (Buchon et al., 2009
). These findings suggest that the loss of damaged ECs stimulates ISC division. Since EB differentiation coincides with a reduction in their contact with a basement membrane, it has also been proposed that this membrane or underlying visceral muscle might provide a niche that promotes stemness and suppresses differentiation (Ohlstein and Spradling, 2007
). Consistent with this, the WNT ligand wg
is expressed in visceral muscle, and is important for ISC survival (Lin et al., 2008
We show here that the Drosophila midgut can rapidly regenerate after enterocytes are ablated, or subjected to enteric infection or stress signaling. Damaged or stressed ECs produce the Unpaired cytokines (Upd, Upd2, Upd3). These ligands and their downstream effectors Domeless (dome, an IL-6R-like receptor), Hopscotch (hop, a Janus Kinase; Jak) and Stat92E (a STAT3-like transcription factor) have important roles in germ stem cell maintenance and the immune response in Drosophila. In the midgut, Upds produced by spent ECs trigger Jak/Stat signaling in ISCs and EBs, promoting their division and differentiation respectively, and thereby driving renewal of the gut epithelium.