Regulation of seminiferous tubule-associated stem Leydig cells in adult rat testes

Abstract

Testicular Leydig cells are the primary source of testosterone in males. Adult Leydig cells have been shown to arise from stem cells present in the neonatal testis. Once established, adult Leydig cells turn over only slowly during adult life, but when these cells are eliminated experimentally from the adult testis, new Leydig cells rapidly reappear. As in the neonatal testis, stem cells in the adult testis are presumed to be the source of the new Leydig cells. As yet, the mechanisms involved in regulating the proliferation and differentiation of these stem cells remain unknown. We developed a unique in vitro system of cultured seminiferous tubules to assess the ability of factors from the seminiferous tubules to regulate the proliferation of the tubule-associated stem cells, and their subsequent entry into the Leydig cell lineage. The proliferation of the stem Leydig cells was stimulated by paracrine factors including Desert hedgehog (DHH), basic fibroblast growth factor (FGF2), platelet-derived growth factor (PDGF), and activin. Suppression of proliferation occurred with transforming growth factor β (TGF-β). The differentiation of the stem cells was regulated positively by DHH, lithium- induced signaling, and activin, and negatively by TGF-β, PDGFBB, and FGF2. DHH functioned as a commitment factor, inducing the transition of stem cells to the progenitor stage and thus into the Leydig cell lineage. Additionally, CD90 (Thy1) was found to be a unique stem cell surface marker that was used to obtain purified stem cells by flow cytometry.

Induction of steroidogenic cells from adult stem cells and pluripotent stem cells [Review]

“…Experimentations were approached through transplantation studies and promoter-sorting analyses using MSCs isolated from rodent bone marrow. Because Leydig cells in the adult testes are known to differentiate until puberty from non-steroidogenic stem cells associated with seminiferous tubules [36][37][38], it was deemed possible to successfully transplant BM-MSCs into this in vivo environment. After 3 weeks, the transplanted BM-MSCs had colonized the interstitium, and whereby they expressed various steroidogenic enzymes similar to endogenous Leydig cells.…”

Mapping lineage progression of somatic progenitor cells in the mouse fetal testis

“…In fact, multiple origins of fetal Leydig cells have been suggested, including Sf1 + nonsteroidogenic interstitial cells originating from the gonadal primordium (Barsoum et al, 2013;Barsoum and Yao, 2010), mesonephros (Merchant-Larios and Moreno-Mendoza, 1998;Val et al, 2006), neural crest (Mayerhofer et al, 1996), coelomic epithelium (Karl and Capel, 1998), and cells residing in the border between gonad and mesonephros (DeFalco et al, 2011). By contrast, it has been suggested that adult Leydig cells stem from peritubular interstitial progenitor cells that arise in the adult testis (Davidoff et al, 2004;Ge et al, 2006;Li et al, 2016;Odeh et al, 2014;Stanley et al, 2012), or from COUP-TFII (Nr2f2)-positive interstitial cells in the fetal testis (Kilcoyne et al, 2014).…”

Transdifferentiation of adult rat stem Leydig cells into prostatic and uterine epithelium, but not epidermis

“…The rodent testis contains SLCs that can form new Leydig cells and restore serum testosterone concentrations when differentiated Leydig cells are removed (Chen et al , 2016; Li et al , 2016). Our current results show that adult rSLCs are also able to differentiate into other non-Leydig cell types in vivo , in this case, prostatic and uterine epithelium, when exposed to appropriate inductive cues from fetal/neonatal mouse mesenchyme from other tissues.…”

“…In contrast, a previous study has shown that nestin-positive SLCs from neonatal mice can be programmed in vitro to form tissues of endodermal, mesodermal and ectodermal origin (Jiang et al , 2014). This may be due to age, experimental conditions ( in vitro vs in vivo ) and/or species of the SLCs used, since Jiang et al used neonatal mouse SLCs, in contrast to our adult rat SLCs (Stanley et al , 2012; Chen et al , 2016; Li et al , 2016). Previous studies have shown that the ability of differentiated epithelium to transdifferentiate decreases with age (Cunha, 1975; 1976).…”

“…These rSLCs can be cultured in undifferentiated states for extended periods, but undergo Leydig cell differentiation when cultured in differentiation-inducing media (Ge et al , 2006). More recently, members of our group identified rSLCs from adult male rats, which could also differentiate into Leydig cells under appropriate culture conditions (Stanley et al , 2012; Li et al , 2016). …”