Abstract
In the last decades, a growing body of evidence has been reported concerning the expression and functional role of hepatocyte growth factor (HGF) on different aspects of testicular physiology. This review has the aim to summarize what is currently known regarding this topic. From early embryonic development to adult age, HGF and its receptor c-Met appeared to be clearly detectable in the testis. These molecules acquire different distribution patterns and roles depending on the developmental stage or the post-natal age considered. HGF acts as a paracrine modulator of testicular functions promoting the epithelium–mesenchyme cross-talk as described even in other organs. Interestingly, it has been reported that testicular HGF acts even as an autocrine factor and that its receptor might be modulated by endocrine signals that change at puberty: HGF receptor expressed by Sertoli cells, in fact, is up-regulated by FSH administration. HGF is in turn able to modify endocrine state of the organism being able to increase testosterone secretion of both fetal and adult Leydig cells. Moreover, c-Met is expressed in mitotic and meiotic male germ cells as well as in spermatozoa. The distribution pattern of c-Met on sperm cell membrane changes in the caput and cauda epididymal sperms and HGF is able to maintain epididymal sperm motility in vitro suggesting a physiological role of this growth factor in the acquisition of sperm motility. Noteworthy changes in HGF concentration in seminal plasma have been reported in different andrological diseases. All together these data indicate that HGF has a role in the control of spermatogenesis and sperm quality either directly, acting on male germ cells, or indirectly acting on tubular and interstitial somatic cells of the testis.
Highlights
THE HEPATOCYTE GROWTH FACTOR MACHINERY AND ITS BIOLOGICAL FUNCTIONS The hepatocyte growth factor (HGF) is a pleiotropic cytokine originally purified as a potent mitogen for hepatocytes [1, 2] and subsequently identified as a “scatter factor” [3, 4]
C-Met is the unique HGF receptor and it is normally expressed by cells of epithelial origin whilst HGF expression has been mainly found restricted to cells of mesenchymal origin. c-Met receptor presents tyrosine-kinase activity and, upon HGF stimulation, this receptor triggers several transduction pathways responsible for its multiple biological responses including proliferation, motility, migration, morphogenesis, tubulogenesis, differentiation, and angiogenesis [8,9,10]
Even if HGF could be mainly identified as paracrine factor in the mesenchyme–epithelium cross-talk, it has been found that this growth factor is actively delivered via blood vessels to injured organs allowing their repair and homeostasis [24, 25]
Summary
THE HEPATOCYTE GROWTH FACTOR MACHINERY AND ITS BIOLOGICAL FUNCTIONS The hepatocyte growth factor (HGF) is a pleiotropic cytokine originally purified as a potent mitogen for hepatocytes [1, 2] and subsequently identified as a “scatter factor” [3, 4]. C-Met c-terminal tail contains tyrosines Tyr 1349 and Tyr 1356, which represent, when phosphorylated, the multifunctional docking site of the receptor These two amino acidic residues are able to recruit several transducers and adaptors after c-Met activation, explaining the whole spectrum of pleiotropic biological activities exerted by HGF/c-Met system [11]. HGF/c-Met system in testicular physiology during the mouse organogenesis has provided great insights in the understanding of HGF function This system, has been found in several developing organs being HGF expressed in the mesenchyme and c-Met in the epithelial part of the developing tissue. ROLES OF HGF IN THE PHYSIOLOGY OF THE TESTIS Hepatocyte growth factor/c-Met system has been found expressed and active during all the phases of pre-natal and post-natal testis development. The emerging picture suggests HGF as one of the growth factors which cooperates at different levels to support male reproductive health and is deeply involved in the harmonic control of spermatogenetic process
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