Peritubular cells provide a window to the human testis and male infertility: Identification as a target for prostaglandins

MAYERHOFER A, SCHELL C, MAYER C, KÖHN F-M, SCHWARZER U, FRUNGIERI MB

Toronto, Canadá

Congreso; 89th Annual Meeting of the Endocrine Society; 2007

Endocrine Society

Pathogenetic events resulting in impaired spermatogenesis and male infertility are not well 1lllderstood, presmnably because the human testis can not be readily studied and relevant models are scarce. We recently reported a technique for isolation and culture of primary human testicular peri tubular cells (HfPCs; 1). These cells are increasingly being recognized to be important for normal testicular f1lllctions. Furthermore they may be structurally and/or f1lllctionally involved in pathological events 1lllderlying male infertility. This hypothesis is based on fibrotic remodelling of the peritubular testicular compartment, a hallmark of male infertility. Importantly, cyc100xygenase 2 (COX2), the rate limiting enzyme of prostaglandin (PG) biosynthesis, is expressed in interstitial cells in testes of infertile men (2) implying formation and action of PGs in states of impaired fertility. Indeed, f1lllctional PG receptors for F2alpha and D2 were described on Leydig cells (3; 4) and profibrotic action of PGJ2 was shown in human fibroblasts (HFFF-2; 2). We therefore now tested whether HfPCs are targets for PGs. By RT -PCR we f01llld evidence for expression of receptors for PGJ2 (PPARgamma), PGE2 (EP1, EP2, EP4) and PGF2alpba (FP). The receptor for PGD2 (DP) and EP3 were not f01llld in HfPCs, but were detected in whole human testes. In HfPCs, PGE2 and PGF2alpha rapidly and transiently increased intracellular calcium levels (Fluo4/confocal microscope), while in MfS assays, only PGJ2 and its non-enzymatic metabolite 15desoxy-PGJ2 increased signal intensity, indicating more and/or larger cells. The latter possibility was shown by results of CASY measurements with diameters of HfPCs being enlarged by 20%. Pilot experiments suggest that PGJ2 treatment also increased mRNA levels of fibronectin and SPARC (secreted protein, acidic, rich in cystein), which may be components of the peri tubular extracellular matrix. The receptor possibly mediating effects of PGJ2 could be PPA, Rgamma which we f01llld by imm1lllofluorescence to be present in at least subpopulations of HTPCs, as well as their in vivo c01lllterparts, peritubular cells of human testes (2). Ongoing studies are exploring this possibility. We propose that in testes of infertile men a consequence of COX2 expression is formation of PGs, which via their specific testicular receptors and mode of actions may directly contribute to the development/maintenance of testicular peri tubular fibrosis by affecting peritubular cells.