© 2012 Landes Bioscience. Do not distribute.

The intestine carries out important func-tions related to digestion and absorption. It is composed of three distinct layers, an outer muscle layer, a mesenchymal layer and the epithelial layer. The epithelial layer forms the protective barrier that faces the luminal content of the intestine. In order to maintain barrier function the epithelial layer needs constant replenish-ment. This is ensured by continuous cel-lular replication in proliferative crypt compartments. Following exit from the crypt, cells adopt fates along either secre-tory or absorptive lineage and will, after three to four days, be exfoliated into the lumen of the intestine from the tips of the villi. Intestinal stem cells located at the bottom of the proliferative crypt compart-ment ensure lifelong maintenance of the organ (Fig. 1A). Adult stem cell niches are far more het-erogeneous than previously anticipated.1 The intestinal stem cell niche can be sub-divided by the relative position within the crypt. Stem cells located in position +4, just above secretory Paneth cells, express HopX, Bmi1 and Tert. These cells are generally less mitotically active than Lgr5-expressing stem cells located at the bottom of the proliferative crypts inter-calated between Paneth cells (Fig. 1A).2,3 It has been argued that both popula-tions represent the most primitive stem cell; however, recent studies suggest that stem cells can interconvert between the two states (Fig. 1B).3 Fate mapping from cells in position 4 and at the bottom of Environmental stimuli and intestinal stem cell behavio