Life in the crypt: a role for glucagon-like peptide-2?

The epithelial layer of the intestinal tract serves as a model to study the mechanisms regulating tissue renewal. Central to this process is the intestinal stem cell and, thus, both the intrinsic and extrinsic factors that modulate the function of these cells must be understood. Amongst the intrinsic regulators, both the canonical wnt and bone morphogenic protein (bmp) signaling pathways have been shown to be essential determinants of stem cell dynamics and intestinal homeostasis. The intestinotrophic hormone, glucagon-like peptide-2 (GLP-2), has also recently been demonstrated to exert a variety of effects on the intestinal crypt cells, including enhancement of the putative stem cell marker, musashi-1, as well as stimulating intestinal proliferation. As the GLP-2 receptor is not expressed by the crypt cells, these actions have been hypothesized to be mediated indirectly, through other gut peptides and/or growth factors. Of these, recent studies have demonstrated a requirement for insulin-like growth factor-1 in the proliferative effects of GLP-2, through a pathway that involves activation of the canonical wnt signaling pathway. This extrinsic pathway represents a novel mechanism by which intestinal stem cell dynamics may be regulated.