The effects of repeated doses of keratinocyte growth factor on cell proliferation in the cellular hierarchy of the crypts of the murine small intestine

Keratinocyte growth factor (KGF) administered on a daily basis for 3 or mor e days can result in dramatic changes in tissue architecture, particularly the thickness in oral epithelia, and can afford protection against the cyto toxic effects of radiation on the clonogenic stem cells in the crypts, This protection of intestinal stem cells (increased numbers of surviving crypts ) is reflected in an increased survival of animals exposed to a lethal dose of irradiation. The mechanisms underlying these effects are not clear. The present experiments were designed to investigate the nature of any prol iferative changes induced in the crypts of the small intestine by protracte d exposure to KGF, Tritiated thymidine or bromodeoxyuridine labeling showed statistically significant increases in labeling in the stem cell zone of t he crypt, with a concomitant reduction in labeling in the upper regions of the crypt corresponding to the late-dividing transit population, The increa se in labeling in the lower regions of the crypt was also observed with Ki- 67 staining, but the reduction in the upper regions of the crypt seen with tritiated thymidine was not observed with Ki-67. Metaphase arrest data sugg est that the rate of progression through the cell cycle is essentially the same in KGF-treated animals as in controls, but there is a statistically si gnificant increase in the number of mitotic events per crypt, Double labeli ng studies suggest that, at certain times of the day, there is a greater in flux into S phase than efflux. The data overall indicate that KGF induces some complex proliferative chang es in the intestinal crypts and are consistent with the hypothesis that the radioprotection may be afforded, at least in part, by a KGF-induced increa se in stem cell numbers and/or increases in the number of stem cells in the S phase of the cell cycle. This alteration in the homeostasis of the crypt is compensated for by a foreshortening of the dividing transit lineage.