Regeneration in epithelial proliferative units as exemplified by small intestinal crypts

Surface epithelia are subdivided structurally into a series of partially autonomous proliferative units. Within each unit the proliferative cells are organized into a lineage or hierarchy each with relatively few ancestral (stem) cells. This structural organization is strikingly illustrated by the gastrointestinal mucosa where the proliferative cells are packaged into crypts. In the mouse small intestine there are 250 cells in total per crypt of which about 150-160 are proliferative. The latter cells are arranged as a series of about 10 rings each of about 16 cells, starting at about the 4th position from the bottom of the crypt and running up to the 13th-14th cell position. The stem cells are believed to be located in the lowermost ring. We have been studying the regenerative process in mouse small intestinal crypts after various levels of injury. Exposure to small doses of cytotoxic agents (e.g. gamma-radiation) reveals that some cells in the stem cell zone are very sensitive but that apparently unaffected cells in the zone are easily disturbed in their cell cycle characteristics by this minor damage. Such observations suggest that some of the controls on stem cell proliferation are extremely local in their action. The stem cells can detect the death of one of their members and the remainder respond accordingly. After more severe injury (drugs or higher doses of radiation) the first detectable changes also appear in the stem cell zone. It is concluded that the crucial cells in the regeneration process in epithelia are the stem cells. The cell kinetic properties during regeneration have been studied experimentally and modelled mathematically.