Leydig cell stem cells: Identification, proliferation and differentiation

Abstract

Adult Leydig cells develop from undifferentiated mesenchymal-like stem cells (stem Leydig cells, SLCs) present in the interstitial compartment of the early postnatal testis. Putative SLCs also have been identified in peritubular and perivascular locations of the adult testis. The latter cells, which normally are quiescent, are capable of regenerating new Leydig cells upon the loss of the adult cells. Recent studies have identified several protein markers to identify these cells, including nestin, PDGFRα, COUP-TFII, CD51 and CD90. We have shown that the proliferation of the SLCs is stimulated by DHH, FGF2, PDGFBB, activin and PDGFAA. Suppression of proliferation occurred with TGFβ, androgen and PKA signaling. The differentiation of the SLCs into testosterone-producing Leydig cells was found to be regulated positively by DHH (Desert hedgehog), lithium-induced signaling and activin; and negatively by TGFβ, PDGFBB, FGF2, Notch and Wnt signaling. DHH, by itself, was found to induce SLC differentiation into LH-responsive steroidogenic cells, suggesting that DHH plays a critical role in the commitment of SLC into the Leydig lineage. These studies, taken together, address the function and regulation of low turnover stem cells in a complex, adult organ, and also have potential application to the treatment of androgen deficiency.

Induced pluripotent stem cell‐derived conditional medium promotes Leydig cell anti‐apoptosis and proliferation via autophagy and Wnt/β‐catenin pathway

“…Testosterone, referred to as the male hormone, plays a critical role in maintaining sexual function, muscle bulk and bone health . Testosterone synthesis in Leydig cells depends on the luteinizing hormone (LH) secreted by the pituitary grand . LH binds LH receptors (LHCGR, encoded by Lhcgr ) on the Leydig cell plasma membrane and then leads to intracellular cyclic adenosine monophosphate (cAMP) cascade, which further results in the rapid transport of cholesterol from the outer to the inner mitochondrial membrane, mediated by lipoprotein receptor (SCARB1, encoded Scarb1 ) and steroidogenic acute regulatory protein (STAR, encoded by Star ).…”

“…3 Testosterone synthesis in Leydig cells depends on the luteinizing hormone (LH) secreted by the pituitary grand. 4 LH binds LH receptors (LHCGR, encoded by Lhcgr) on the Leydig cell plasma membrane and then leads to intracellular cyclic adenosine monophosphate (cAMP) cascade, 5 which further results in the rapid transport of cholesterol from the outer to the inner mitochondrial membrane, mediated by lipoprotein receptor (SCARB1, encoded Scarb1) and steroidogenic acute regulatory protein (STAR, encoded by Star). Subsequently, testosterone is synthesized through a series of steroidogenic enzymes: the cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A1, encoded by Cyp11a1), 3b-hydroxysteroid dehydrogenase (HSD3B1, encoded by Hsd3b1), cytochrome P450 17a-hydroxylase (CYP17A1, encoded by Cyp17a1) and 17b-hydroxysteroid dehydrogenase 3 (HSD17B3, encoded by Hsd17b3), 6 while another critical factor for Leydig cells is the steroidogenic factor 1 (SF-1, or named NR5A1), which is essential for the commitment of stem Leydig cells to testosterone-producing Leydig cells.…”

Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors

“…This model has allowed investigators to identify factors that regulate Leydig cell differentiation (Molenaar et al 1986, Yan et al 2000, Sriraman et al 2003, Salva et al 2004, O’Shaughnessy et al 2008, Zhang et al 2013, O’Shaughnessy et al 2014, Lobo et al 2015, Zhang et al 2015). Additionally, the EDS model has shed light on stem Leydig cells present in peritubular and perivascular locations within the testicular interstitium (Kilcoyne et al 2014, Chen et al 2017). One limitation of EDS is that it does not cause Leydig cell destruction in mice except at high doses that may be associated with additional off-target effects (Smith et al 2015).…”

Exposure to cadmium during gestation and lactation affects development and function of Leydig cells in male offspring

“…Leydig cells are testosterone‐producing cells locating in testicular interstitium among the seminiferous tubule. Four distinct stages in the development of Leydig cell have been identified: the stem Leydig cells (SLCs), progenitor Leydig cells (PLCs), immature Leydig cells (ILCs) and adult Leydig cells (ALCs) . SLCs usually appear at postnatal day (PND) 7 in spindle‐shape with few smooth endoplasmic reticulums (SERs).…”