Human testicular peritubular cells exert anti-angiogenetic action: A role for pigment-epithelium derived factor (PEDF) in the maintenance of avascular seminiferous tubules, the blood-testis barrier and the spermatogonial stem cell niche in man?

Abstract

Male fertility depends on spermatogenesis, which takes place in the seminiferous tubules. This compartment is devoid of blood vessels, yet the peritubular capillary network is an important part of the spermatogonial stem cell niche, as suggested by studies in mouse. Our proteomic studies of cultured human testicular peritubular cells (HTPCs) revealed that they constitutively secrete pro-angiogenetic factors (e.g. VEGF) and the anti-angiogenetic factor, pigment epithelium derived factor, PEDF. This factor has not previously been reported in the human testis. Immunohistochemistry performed with human testicular samples revealed that it is present in vivo, in the peritubular wall. Cellular co-culture studies, using HTPCs and human endothelial cells (HUVEC), and migration analysis showed that HUVECs are repulsed by HTPCs. The factor involved is likely PEDF and its actions were abolished by a PEDF-antiserum. Heat-inactivation of the antiserum reverted this action. Gene expression analysis revealed that PEDF is expressed in the testis of a non-human primate before puberty suggesting involvement in the establishment and maintenance of the distinct vascular pattern of seminiferous tubules and of its overall avascular nature. Addition of dihydrotestosterone to HTPCs increased PEDF (qPCR), indicating that it is subject to hormonal modulation. Thus, testicular peritubular cells prevent vascularization of human seminiferous tubules by secreting the anti-angiogenetic protein PEDF. However, fine-tuning of its production (e.g. by androgens) may bring about local differences in the control of testicular interstitial microvessels and thereby possibly may influence the spermatogonial stem cell niche. (Supported by DFG MA1080/20 – 1; FOR1041)