Gastrointestinal cell proliferation and crypt fission are separate but complementary means of increasing tissue mass following infusion of epidermal growth factor in rats

Background and aims-Epidermal growth factor (EGF) is a potent mitogen for t he gastrointestinal tract and also influences the number of new crypts form ed by crypt fission. The time course of these events and possible linkage b etween these two complementary mechanisms is however poorly understood. We therefore examined the temporal relationship of proliferation and fission i n rats treated with EGF. Methods-Osmotic minipumps were implanted subcutaneously into male Wistar ra ts to infuse EGF continuously (60 mug/rat/ day) for periods of 1-14 days. P roliferation and crypt branching were quantified following vincristine indu ced metaphase arrest and morphometric assessment of microdissected tissue. Results-In the small intestine, EGF significantly increased epithelial cell . proliferation and crypt and villus area after 24 hours of EGF, although m aximal effects were only reached following six days of infusion. EGF also r esulted in an approximate 30% reduction in crypt fission in the small bowel . In the colon, EGF caused a twofold increase in epithelial cell proliferat ion one day after infusion, from 15.3 (2.3) to 29.6 (3.5) metaphases per cr ypt (p <0.01). Maximal effects were seen in rats receiving EGF for seven da ys. For all time points, colonic crypt size increased in response to EGF Th e amount of branching increased following one day of infusion with EGF (fro m 15.3 (1.9) to 32.4 (5.5)%; p <0.001) but was significantly lower (approxi mately 25% of control values) following longer periods of infusion. Crypt f ission did not correlate with crypt area. Conclusion-EGF has profound effects on cell proliferation and also altered crypt fission, with its actions on crypt fission most pronounced in the col on where it first increased and then decreased fission. EGF can thus be a p otent stimulus for crypt fission during short term infusion and may reduce the number of branched crypts present in a resting or quiescent stage. Grow th factors can alter cell mass by two separate but linked mechanisms, namel y altered cell production and crypt fission.