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Studies on Mesenchymal growth factors during postnatal growth of the small intestine

Postnatal growth of the small intestine can be divided into two separate but complementary mechanisms; mucosal growth and organ (cylindrical) growth. Mucosal growth, observed by increasing villus area and crypt length, is upregulated during weaning, compared to pre or post-weaned time frames. The dynamics of organ growth, mediated by the process of crypt fission, is unknown during this period of postnatal development. Keratinocyte Growth Factor (KGF) and Hepatocyte Growth Factor (HGF) are mesenchymally derived ligands which have been demonstrated to have trophic effects on the epithelium of the gastrointestinal tract in vitro and in vivo during embryonic development, repair/restitution and tumour progression. This study explores the hypothesis that small intestine organ growth occurs independently to that of mucosal growth and the mechanisms of growth are mediated by differential expression of either HGF or KGF within the pericryptal mesenchyme derived cells (fibroblasts). Alternatively, the corresponding receptors for these ligands, c-met and bek, may exhibit differential expression within the proliferative compartment of the crypts. The indices of mucosal and organ growth were compared at various ages during early postnatal life (suckling), then early, middle and late weaning through to adult animals. Microdissection techniques utilising whole tissue samples enabled microscopic evaluation of growth. The assessment of KGF, bek, HGF and c-met was also undertaken using immunohistochemistry on formalin fixed, paraffin processed sections of rat jejunum. The highest rate of organ growth occurred during weaning and was immediately preceded at day 14 (of age) by a peak in the incidence of branching crypts. KGF immunolabelling was observed within the mesenchymal cells at the tips of the villus from mid-weaning onwards but at no stage within pericryptal fibroblasts. Both KGF and bek were demonstrated within the crypt epithelium, with highest levels observed during weaning. Immunolabelling for HGF demonstrated an ubiquitous distribution within both epithelial and mesenchymal tissues at all ages, whilst the expression of c-met was in the crypt cell compartment was limited to the time of weaning. The use of an in vivo blockade technique utilising an anti-HGF (D9) antibody from age 7 to 14 days did not demonstrate any reduction of the indices of organ or mucosal growth. These results suggest that rate of organ and mucosal growth increase concurrently during weaning. The demonstration of both bek and c-met in the crypt cell population during this period suggests that KGF and HGF are potential mediators of organ or mucosal growth, despite only HGF being demonstrated in the pericryptal mesenchymal derived cells. Further, the expression of KGF and HGF at sites beyond the crypts suggest these ligands play a greater role in the development of the rat small intestine during postnatal growth. / thesis (MApSc(BiomedicalScience))--University of South Australia, 2005.
Date January 2005
CreatorsGordon, Colin R
Source SetsAustraliasian Digital Theses Program
Detected LanguageEnglish
Rights© 2005 Colin Gordon

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