Hepatocyte Growth Factor Is a Mouse Fetal Leydig Cell Terminal Differentiation Factor1

Abstract

The hepatocyte growth factor (HGF) is a pleiotropic cytokine and a well-known regulator of mouse embryonic organogenesis. In previous papers, we have shown the expression pattern of HGF and its receptor, C-MET, during the different stages of testis prenatal development. We demonstrated that C-MET is expressed in fetal Leydig cells (FLCs) and that HGF stimulates testosterone secretion in organ culture of late fetal testes. In the present study, we analyzed the proliferation rate, apoptotic index, and differentiation of FLCs in testicular organ culture of 17.5 days postcoitum (17.5 dpc) embryos to clarify the physiological role of HGF in late testis organogenesis. Based on our data, we conclude the following: 1) HGF acts as an antiapoptotic factor that is able to reduce the number of apoptotic FLCs and testicular caspase-3 active fragment; 2) HGF does not affect FLC proliferation; 3) HGF significantly increases expression of insulin-like 3 (INSL3), a marker of Leydig cell terminal differentiation, without affecting 3beta-hydroxysteroid dehydrogenase (3betaHSD) expression; 4) HGF significantly decreases the expression of nestin, a marker of Leydig cell progenitors; and 5) HGF significantly increases the number of fully developed FLCs. Taken together, these observations demonstrate that HGF is able to act in vitro as a survival and differentiation factor in FLC population.

Development, function and fate of fetal Leydig cells

“…HGF is localized in the connective tissue of the interstitial compartment in E18.5 fetal testes, but it is not expressed by FLCs, while its receptor met proto-oncogene (MET, also known as c-MET, a glycoprotein with tyrosine kinase activity) is expressed in FLCs during late fetal testis development. HGF is known to promote FLC terminal development and protect FLCs from apoptosis in fetal testis development [30] (Fig. 2).…”

Leydig cell stem cells: Identification, proliferation and differentiation

“…The subsequent appearance of Leydig cells was associated with reduced nestin expression. This developmental relationship between Leydig cell maturation and loss of nestin expression also was found in the fetal testis (Ricci et al, 2012) and in the early postnatal testis (Jiang et al, 2014). …”

Mesenchymal stem cells from human umbilical cord ameliorate testicular dysfunction in a male rat hypogonadism model

“… 19 20 21 These cellular factors can then promote the regeneration of Leydig cells and enhance their functions. 17 18 22 In the present experiment, transplanted HUMSCs may have released or promoted the release of certain factors that guided the regeneration of Leydig cells. HUMSCs, compared with BMSCs, possess a higher proliferative potential, and HUMSCs are more capable of differentiating into Leydig cells.…”