Are testicular mast cells involved in the regulation of germ cells in man?

Abstract

Protease activated receptor-2 (PAR-2) is the receptor for the prototype mast cell product tryptase. PAR-2 expression by cells of the human germinal epithelium was reported, but the exact cellular sites of testicular expression remained unknown. That became of interest, because mast cells, expressing tryptase, were found in the walls of seminiferous tubules of patients suffering from sub-and infertility. This location suggested that mast cells via tryptase might be able to influence PAR-2-expressing cells in the germinal epi-thelium. To explore these points, we used testicular paraffin-embedded sections for immunohistochemistry. PAR-2-positive cells were mostly basally located cells of the seminiferous epithelium, namely spermatogonia. Some stained for the receptor for GDNF (GFRalpha-1), and possibly represent spermatogonial stem cells (SSCs). As true human SSCs could not be examined, we turned to TCam-2 seminoma cells, expressing PAR-2 and stem cell markers, including GFRalpha-1. TCam-2 cells robustly responded to stimulation with a specific PAR-2 agonist (SLIGKV) by increased intracellular Ca 2+ levels. Recombinant tryptase and trypsin, but not a control peptide (VKGILS) evoked this response, implying functional PAR-2. Video imaging and caspase 3/7 assays showed that SLIGKV and tryptase prevented spontaneous apoptosis and increased proliferation of TCam-2 cells. The expression of the marker of pluripo-tency OCT3/4 was unchanged upon activation of PAR-2, suggesting that the stem cell-like character is not changed. Furthermore, human germ cell cancers were examined. A subset of seminoma and carcinoma in situ samples expressed PAR-2, indicating that yet unknown subgroups exist. Collectively, the descriptive data obtained in human testicular sections, in germ cell cancers and the functional results in TCam-2 cells imply a trophic role of mast cell-derived tryptase for human germ cells. This may be relevant for sub-types of human germ cell cancers, and possibly SSCs. It also raises the possibility that PAR-2 agonists might be useful for the in vitro propagation of human SSCs.

The Cellular Impact of the ZIKA Virus on Male Reproductive Tract Immunology and Physiology

“…In addition to BTB and anatomical impairment of external cells' and molecules' entrance to testis, SCs also provide anti-inflammatory mediator secretion aiming to maintain the tolerogenic microenvironment [8]. However, many local immune modulators, including macrophages, dendritic cells (DCs), natural killer cells (NKs), mast cells and T-lymphocytes, contribute to the intercommunication among testicular components [9][10][11][12]. The testis is composed of interstitial LCs located between blood vessels and the seminiferous tubules, where sperm is produced [25].…”

Correlation between testicular mast cell count and spermatogenic epithelium in non‐obstructive azoospermia

“…Nevertheless, a possible trophic action of MCs in seminiferous tubules of infertile cases was mentioned by Windschuttl et al . () possibly by secreting tryptase that may influence spermatogonia expressing protease‐activated receptor‐2. In addition, Adam et al .…”

“…Our findings showed that the increased MCs in testicular biopsies of MA and GCA patients are negatively correlated with Johnsen score and Ki67 index but positively correlated with vimentin expression in Sertoli cells. Nevertheless, a possible trophic action of MCs in seminiferous tubules of infertile cases was mentioned by Windschuttl et al (2014) possibly by secreting tryptase that may influence spermatogonia expressing protease-activated receptor-2. In addition, Adam et al (2011) have demonstrated small amounts of the ECM protein decorin (DCN) in the wall of normal seminiferous tubules.…”

Significance of mast cells in spermatogenesis, implantation, pregnancy, and abortion: Cross talk and molecular mechanisms

“…PAR‐2 expressing spermatogonia in seminiferous epithelium could be influenced by tryptase‐releasing MCs . Investigations on TCam‐2 seminoma cells with high expression levels of PAR‐2 showed that tryptase prevents apoptosis and supports their proliferation . Sezer et al reported the elevated expression levels of iNOS in Leydig cells correlate with MC index in Sertoli cell‐only syndrome (SCO) and severe damage of the germ cell .…”