Gut instincts: thoughts on intestinal epithelial stem cells.

surface of the gastrointestinal tract is lined by a simple columnar epithelium that is folded to form a number of invaginations, or crypts, that are embedded in the connective tissue. Each crypt contains approximately 250 cells, depending on its species and anatomical location. Crypt size and organization are generally uniform within a given region of the gastrointestinal tract (1). Of the major gut epithelial cell types, all but one (the Paneth's cells of the small intestine) move upward toward the lumen of the gut as they mature. Hence, the differentiated, functional cells are found mainly on the villi (small intestine) or toward the top of the colonic crypt — the intercrypt table — in the large intestine. During the latter stages of the process, these mature epithelial cells become senescent and are shed intact into the lumen. Cells shed from the gut must be replaced by a steady supply of cells generated in the low-to mid-crypt region, where, at least in the mouse, up to 60% of the crypt cells divide twice daily. Because of this continuous upward migration, the location of a cell within the migratory stream indicates its stage in the process of maturation. Intestinal stem cells reside at the origin of the migration, which is found just above the crypt base in the small intestine and at the crypt base in the colon (2). As with normal homeostatic proliferation, crypt regeneration after cytotoxic damage also appears to originate at this site. Unfortunately, the stem cells responsible for tissue homeostasis and regeneration cannot be identified morphologically or distinguished from other epithelial cells by any recognized set of markers. Hence, most interpretations of stem-cell behavior are based upon monitoring cohorts of cells before and after perturbation of the tissue. This approach offers direct insights into the dynamics of the crypt-cell population, but only limited steady-state behavioral information on the cells themselves. This limitation may be inevitable in the absence of good molecular markers, but it must be kept in mind when interpreting many current experiments. Estimates of stem-cell number vary widely, from 0.4% to 60% of the crypt cells, with the smallest value implying that a single stem cell occurs in each crypt. This discrepancy arises largely because of differences in the operational definition of the stem cell. It is now generally accepted that " stemness " is not a single property, but a number of properties that can …