Intestinal stem cell function in Drosophila and mice

Epithelial cells of the digestive tracts of most animals are short-lived, and are constantly replenished by the progeny of long-lived, resident intestinal stem cells. Proper regulation of intestinal stem cell maintenance, proliferation and differentiation is critical for maintaining gut homeostasis. Here we review recent genetic studies of stem cell-mediated homeostatic growth in the Drosophila midgut and the mouse small intestine, highlighting similarities and differences in the mechanisms that control stem cell proliferation and differentiation.

Introduction

The endodermal portion of the insect intestine, termed the midgut, and its mammalian counterpart, comprising the stomach, small intestine and colon, serve as the animal's principal organs for digestion and nutrient absorption. In the mammalian small intestine, absorptive enterocytes and secretory goblet and enteroendocrine cells reside in finger-like protrusions known as villi. These cells are short-lived, being constantly shed from the villi and replaced by new cells generated in neighboring invaginations called the Crypts of Lieberkühn. The intestinal epithelium is perhaps the most rapidly turned over tissue in mammals, with enterocyte lifespans averaging a week or less. Intestinal stem cells (ISCs) reside at the basal ends of the crypts, intermingled with long-lived Paneth cells of the secretory lineage (Figure 1a). ISCs proliferate to self-renew and also give rise to transient progeny that amplify through further divisions. As cells exit the crypts and move apically, they differentiate into either absorptive enterocytes or one of three types of secretory cells: Paneth, enteroendocrine, or goblet. The mammalian colon is similarly maintained by ISCs located in crypts, but villi are absent and replaced by a smooth epithelium. In addition to these endodermal cells produced by ISCs, the mammalian intestine has stromal cells of several types – mesenchymal fibroblasts, immune cells and others – and is surrounded by mesodermally derived visceral muscle.

The endodermal portion of the Drosophila intestine, termed the midgut, undergoes similar dynamic cell turnover, also mediated by long-lived intestinal stem cells [1•, 2•]. The fly midgut however lacks crypts and villi, instead comprising a cellular monolayer ensheathed by two orthogonal layers of visceral muscle. Intestinal stem cells reside at the basal side of this epithelium, sandwiched between enterocytes and basement membrane produced partly by visceral muscle (Figure 1b). They divide to self-renew and to give rise to committed progenitors (called enteroblasts), which directly differentiate, without cell division, into two functional cell lineages similar to those found in vertebrates: absorptive enterocytes and enteroendocrine cells. Differentiating enterocytes endoreplicate their genome 2–3 times to increase their size and develop a brush border similar to that in mammals. Drosophila lacks the Paneth, Goblet, Stromal, and Dentritic cells found in mammals, but some of their functions – such as immunity and barrier production – are fulfilled by enterocytes. Instead of the thick mucosa produced by mammalian goblet cells, insect intestines have a tough but relatively thin (∼200 μm) membrane called the peritrophic matrix. This matrix is comprised of the exoskeletal protein chitin and glycoproteins including mucins related to those found in vertebrate mucosa, and it provides an essential barrier against infection by enteric pathogens [3].