Spatial and Temporal Patterns of Expression of Epidermal Growth Factor, Transforming Growth Factor Alpha and Transforming Growth Factor Beta 1-3 and Their Receptors in Mouse Jejunum after Radiation Treatment

The goal of the present study was to assess changes in proliferation in the mouse jejunum after irradiation and the role of the growth factors EGF, TGF-α and ${\rm TGF}\text{-}\beta _{1-3}$ in the proliferative response. Our working hypothesis was that feedback signals from the villus to cells in the crypt regulate proliferation, and that the growth factors EGF and TGF-α with their common receptor EGF-R are involved in stimulation of proliferation, while the growth factors ${\rm TGF}\text{-}\beta _{1-3}$ with their receptors TGF-βRI and TGF-βRII are involved in inhibition of proliferation during this regulation. Immunohistochemical detection methods and automated image analysis were used for objective quantification of growth factor expression. The data indicate that, after 5 Gy irradiation, growth stimulation in the crypts takes place before major changes in the villi are observed. However, the combination of the reduction in the cell number, the number of cells expressing ${\rm TGF}\text{-}\beta _{1-3}$ and the reduction in the level of expression of ${\rm TGF}\text{-}\beta _{1-3}$ in the villi may cause the release of crypt cells from regulatory growth inhibition and initiate a proliferation-stimulating signal by an increase in the production of TGF-α and EGF. Regulation of proliferation after initiation of a proliferative response seems to be related more to the growth factors EGF, TGF-α and ${\rm TGF}\text{-}\beta _{3}$ in the crypts than to villus cellularity or growth factor expression, supporting the concept of stem cell autoregulation as a mechanism of cell regeneration in the intestinal crypt.