Ageing of murine small intestinal stem cells.

Most organs of the body comprise populations of cells that are committed to specialized functions and that are renewed from small numbers of uncommitted progenitor or 'stem' cells. Stem cells are of central importance in the study of ageing because any senescent decline in the number or functional competence of stem cells will impair the capacity for renewal and turnover of committed cells, with potentially serious consequences for tissue homeostasis. The intestinal epithelium represents an excellent model system for the study of stem cells. Its spatial and hierarchical organisation allows the study of the function or characteristic of a given cell according to its position within the crypt. Hence, the stem cells which are located at the 4th-5th cell position from the bottom can be studied together with their daughter cells, as they divide and differentiate while migrating along the crypt-villus axis. The ability of the stem cells to undergo apoptosis and the capacity to regenerate the epithelium following injury were investigated in mice of different ages. Stem cells from older animals showed an increased apoptotic response following exposure to low doses of ionising radiation. The regenerative capacity was estimated by measuring the crypt survival levels and the growth rate of surviving crypts after high doses of irradiation. Surviving crypts in the older mice, suggesting an impairment in the damage recognition/response mechanisms, were both fewer and smaller than in young mice. The growth rate of surviving crypts was determined by measuring the crypt area and the number of cells/crypt at various times after 14 Gy irradiation. There was a growth delay of between half and one day in the older mice, and they subsequently grew more slowly. The number of cells susceptible to regenerate a crypt was also estimated. Surprisingly, they appear to be more numerous in the older mice. These studies indicate important age-related alterations in the capacity of the stem cells to regenerate the crypts after radiation-induced damage. The molecular bases of these changes are currently being investigated. Preliminary data showed alteration in the level of p53 and p21 expression, suggesting an age-related defect in the capacity to recognize damage and initiate apoptosis or repair.