Functions of fibroblast and transforming growth factors in primary organoid-like cultures of normal human urothelium.

Previous studies have indicated that growth factors such as epidermal growth factor, transforming growth factor alpha, and fibroblast growth factor 1 (FGF-1) have important regulatory functions in murine urothelial wound healing and tumorigenesis. Immunocytochemical analyses suggest that these factors are also involved in human urothelium. Yet, little is known about the functional effects of these growth factors on human urothelial cells. We established organoid-like primary cultures of normal human urothelium on porous membranes. Direct functional effects of growth factors were examined on confluent cultures reflecting intact urothelium. Immunocytochemistry was performed with a panel of specific antibodies against growth factors and their receptors on both cultures and the corresponding tissue sections. Lacking the appropriate antibodies, we performed reverse transcriptase PCR to detect FGF receptor mRNA in cultures and dissected tissue. The proliferation was stimulated by transforming growth factor alpha, FGF-1, and weakly by FGF-7, but not by FGF-2. TGF beta 1 inhibited proliferation. In contrast to mouse urothelium, none of the growth factors showed an effect on differentiation. The functional data correlate with the urothelial expression of epidermal growth factor receptors, TGF beta receptor types I and II, the (low) protein expression of FGF receptor 1, and the presence of FGF-7 receptor (FGF receptor 2 (IIIb)) mRNA. The organotypic nature of the cultures permits the study of growth factor interactions between urothelial cells. The data indicate that FGF-1, transforming growth factor alpha, and TGF beta 1 contribute differently to the maintenance of human urothelium.