Partial loss of contractile marker proteins in human testicular peritubular cells in infertility patients

Abstract

Fibrotic remodelling of the testicular tubular wall is common in human male infertility caused by impaired spermatogenesis. We hypothesized that this morphological change bears witness of an underlying fundamentally altered state of the cells building this wall, that is, peritubular smooth muscle-like cells. This could include a loss of the contractile abilities of these cells and thus be a factor in male infertility. Immune cells are increased in the tubular wall in these cases, hence local immune cell-related factors, including a prostaglandin (PG) metabolite may be involved. To explore these points in the human, we used testicular biopsies, in which tubules with normal spermatogenesis and impaired spermatogenesis are next to each other [mixed atrophy (MA)], normal biopsies and cultured human testicular peritubular cells. Proteins essential for contraction, myosin heavy chain (MYH11), calponin (Cal) and relaxation, cGMP-dependent protein kinase 1 (cGKI), were readily detected by immunohistochemistry and were equally distributed in all peritubular cells of biopsies with normal spermatogenesis. In all biopsies, vascular smooth muscle cells also stained and served as important intrinsic controls, which showed that in MA samples when spermatogenesis was impaired, staining was restricted to only few peritubular cells or was absent. When spermatogenesis was normal, regular peritubular staining became obvious. This pattern suggests complex regulatory influences, which in face of the identical systemic hormonal situation in MA patients, are likely caused by the local testicular micromilieu. The PG metabolite 15dPGJ2 may represent such a factor and it reduced Cal protein levels in peritubular cells from patients with/without impaired spermatogenesis. The documented phenotypic switch of peritubular, smooth muscle-like cells in MA patients may impair the abilities of the afflicted seminiferous tubules to contract and relax and must now be considered as a part of the complex events in male infertility.