Rolle der Mastzellen und Decorin für die normale und gestörte Hodenfunktion
Final Report Abstract
The results of project provide novel information about specific features of testicular MCs in man, about the interaction of MCs with testicular peritubular cells and the regulation and role of testicular DCN: We described that testicular MCs in certain cases of male infertility contain the rate-limiting enzyme for the synthesis of prostaglandins, COX2, and are thus a novel source of testicular prostaglandins. A metabolite of prostaglandin D furthermore reduced expression of contractility proteins in HTPCs. The protease chmyase was located in testicular MCs in testes of infertile men. It converts ANG1 to the active hormone ANGII, for which receptors AT1R were located in peritubular cells in vivo. In HTPCs stimulation of AT1R caused contractions and the production of IL-6. This is a unique situation in infertile men and since drugs interfering with this pathway are common for the treatment for hypertension, the results bear translational significance. Melatonin receptors were also located in human testicular MCs and were linked to oxidative stress. Although MC did not reveal receptors for sex steroids, the studies led to the unexpected insight that HTPCs in vivo and in vitro express the membrane associated receptor for estrogens (GPER) in a development/fertility–dependent fashion, implying a role of estrogens and this receptor in the human testis. The mast cell/macrophage product TNFalpha stimulated DCN- secretion from HTPCFs. This ECM-factor thus may be linked to the activity of MCs and (due to its interference with growth factor systems) to human male infertility. While such actions can be shown in cellular studies with human cells, and are in line with changes observed during testicular development in a non-human primate species, the studies in the systemic mouse model were sobering: The crossing between DCN-/- and AROM+ mice did not alter the testicular phenotype, i.e. the impairment of spermatogenesis and the testicular inflammation. Thus, in mice DCN is most likely not a testicular factor of importance for male infertility. The lack of an action of DCN in the systemic mouse study makes as reluctant to pursue this line of research at this point in time. It must be mentioned at this point however that the sister molecule of DCN, namely biglycan (BGN) is subject of an ongoing project and pending on the evolving data, a follow up-study may arise in the future.
Publications
- Mast Cells and Their Evolving Role in the Human Testis. Book chapter (eBook) in: Mast Cells: Phenotypic Features, Biological Functions and Role in Immunity Chapters Books, Nova Science Publishers, Authors / Editors: David B. Murray
Artur Mayerhofer, Christoph Schell, Katrin Spinnler, Marion Adam and Harald Welter
- Mast cells in human testicular biopsies from patients with mixed atrophy: increased numbers, heterogeneity, and expression of cyclooxygenase 2 and prostaglandin D2 synthase. Fertil Steril. 2011;96(2):309-13
Welter H, Köhn FM, Mayerhofer A
- High levels of the extracellular matrix proteoglycan decorin are associated with inhibition of testicular function. Int J Androl. 2012;35(4):550-61
Adam M, Urbanski HF, Garyfallou VT, Welsch U, Köhn FM, Ullrich Schwarzer J,Strauss L, Poutanen M, Mayerhofer A
(See online at https://doi.org/10.1111/j.1365-2605.2011.01225.x) - Human testicular peritubular cells: more than meets the eye. Reproduction. 2013;145(5):R107-16
Mayerhofer A
(See online at https://doi.org/10.1530/REP-12-0497) - Partial loss of contractile marker proteins in human testicular peritubular cells in infertility patients. Andrology. 2013;1(2):318-24
Welter H, Kampfer C, Lauf S, Feil R, Schwarzer JU, Köhn FM, Mayerhofer A
(See online at https://doi.org/10.1111/j.2047-2927.2012.00030.x) - Angiotensin II regulates testicular peritubular cell function via AT1 receptor: a specific situation in male infertility. Mol Cell Endocrinol. 2014;393(1-2):171-8
Welter H, Huber A, Lauf S, Einwang D, Mayer C, Schwarzer JU, Köhn FM, Mayerhofer A
(See online at https://doi.org/10.1016/j.mce.2014.06.011) - Expression of the oestrogen receptor GPER by testicular peritubular cells is linked to sexual maturation and male fertility. Andrology. 2014 ;2(5):695-701
Sandner F, Welter H, Schwarzer JU, Köhn FM, Urbanski HF, Mayerhofer A
(See online at https://doi.org/10.1111/j.2047-2927.2014.00243.x) - Melatonin in testes of infertile men: evidence for anti-proliferative and anti-oxidant effects on local macrophage and mast cell populations. Andrology. 2014;2(3):436-49
Rossi SP, Windschuettl S, Matzkin ME, Terradas C, Ponzio R, Puigdomenech E, Levalle O, Calandra RS, Mayerhofer A, Frungieri MB
(See online at https://doi.org/10.1111/j.2047-2927.2014.00207.x)
