Compensatory paracrine mechanisms that define the urothelial response to injury in partial bladder outlet obstruction

Abstract

Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo. To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.

Fibroblast growth factor-10 signals development of von Brunn's nests in the exstrophic bladder

“…8C) according to three criteria: 1) spindleshaped cellular morphology, 2) correlation with the bluestained fibrillar collagen (type I or III) in Masson's trichromestained sections (Fig. 1), and 3) synthesis of FGF-10, an observation in agreement with our prior reports (2,25,27,58).…”

“…Mice of the C57BL/6J strain that contained a targeted disruption to the FGF7 gene were obtained from E. Fuchs (Rockefeller University) and bred to yield colonies of homozygous (Ϫ/Ϫ) mice (19,20,27). Erythematous skin and matted fur were noted in FGF7-null mice injected with rFGF-7, as previously noted (19).…”

“…3, F and L, respectively) led us to hypothesize that nested cells would express markers of pathways involved in the proliferation of basal urothelial cells of transitional epithelia. One such pathway is the paracrine network of FGF-10, its tyrosine kinase cell-surface receptor, and an undefined nuclear receptor, which are known to operate within urothelial cells, as described in our prior reports (2,25,27,58).…”

“…The best-studied FGF in the urinary bladder is FGF-10, a 22-kDa polypeptide which is expressed in lamina propria and transported to the urothelium, where it interacts with its cell surface receptor to stimulate urothelial cell proliferation (2,58). The FGF-10 pathway is the principal compensatory paracrine mechanism that defines the urothelial response to injury in partial bladder outlet obstruction (27). Because recombinant FGF-10 therapy is able to rescue a deficient urothelium found in mice that harbor a targeted disruption of the FGF-7 gene (2), the growth factor is considered to have significant clinical potential.…”

Directed differentiation of human induced pluripotent stem cells into mature stratified bladder urothelium

“…Interestingly, FGF7, another ligand of FGFR2IIIb, also enhanced the stratification of urothelium in mice, similar to FGF10, but suppressed the differentiation of urothelium 44 , in contrast to FGF10. FGF7 is considered to originate in the mesenchyme and be active at the urothelium 45 . FGF7 from mesenchyme may thus cause the negative expression of uroplakins in the basal region of urothelium.…”