McCarthy, L.S.L.; (2006) Extracellular matrix biology in normal and abnormal bladder development. Doctoral thesis , University of London.

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Abstract

Previous work demonstrated that fibronectin is expressed in embryonic mouse detrusor smooth muscle cells (DSMC). Integrins are cell surface receptors for extracellular matrix (ECM) molecules, including fibronectin. The general hypothesis explored here is that ECM/integrin interactions are important in normal and pathological DSMC differentiation. The first specific hypotheses tested were that the candidate fibronectin receptor integrin a5pi and the laminin 1/2 candidate receptor integrin a7pi are expressed by developing DSMC, Using immunohistochemistry, Western blots, and flow cytometry, these proteins were found to be expressed during murine bladder differentiation. This led to the second specific hypothesis, namely that embryonic nascent DSMC adhere to fibronectin, a process mediated by integrin a5 31. Fibronectin substrate was shown to enhance the adhesion of disaggregated embryonic mouse bladder cells. Blocking integrin receptors using RGD oligopeptides modestly but significantly decreased adherent cells expressing desmin, and reduced cell spreading. To explore roles for fibronectin in whole bladders, rather than isolated cells, embryonic mouse organ cultures were established which recapitulated some in vivo differentiation features. However, no specific effects on growth or differentiation could be demonstrated using presumed Tibronectin-blocking' antibodies. Time did not allow testing of RGD oligopeptides. Last, the following hypotheses were explored: that fibronectin is expressed during normal human fetal DSMC differentiation, and that this pattern is altered in bladders from fetuses with presumed bladder outflow obstruction. Fibronectin was indeed found to be expressed during normal human detrusor differentiation and its expression was sometimes reduced in malformed human fetal bladders. These studies provide further descriptive, and hence circumstantial, evidence that ECM/integrin interactions may be important in normal DSMC development. Further studies are warranted to resolve the apparently conflicting/ambiguous organ and cell culture data regarding possible roles for fibronectin and its receptors. The studies also provide preliminary evidence of abnormal fibronectin expression in human congenital bladder anomalies.

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