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Androgen deficiency (hypogonadism) affects males of all ages. Testosterone replacement therapy (TRT) is effective in restoring serum testosterone and relieving symptoms. TRT, however, is reported to have possible adverse effects in part because administered testosterone is not produced in response to the hypothalamic-pituitary-gonadal (HPG) axis. Progress in stem cell biology offers potential alternatives for treating hypogonadism. Adult Leydig cells (ALCs) are generated by stem Leydig cells (SLCs) during puberty. SLCs persist in the adult testis. Considerable progress has been made in the identification, isolation, expansion and differentiation of SLCs in vitro. In addition to forming ALCs, SLCs are multipotent, with the ability to give rise to all 3 major cell lineages of typical mesenchymal stem cells, including osteoblasts, adipocytes, and chondrocytes. Several regulatory factors, including Desert hedgehog and platelet-derived growth factor, have been reported to play key roles in the proliferation and differentiation of SLCs into the Leydig lineage. In addition, stem cells from several nonsteroidogenic sources, including embryonic stem cells, induced pluripotent stem cells, mature fibroblasts, and mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord have been transdifferentiated into Leydig-like cells under a variety of induction protocols. ALCs generated from SLCs in vitro, as well as Leydig-like cells, have been successfully transplanted into ALC-depleted animals, restoring serum testosterone levels under HPG control. However, important questions remain, including: How long will the transplanted cells continue to function? Which induction protocol is safest and most effective? For translational purposes, more work is needed with primate cells, especially human., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

It was reported previously that adult mouse stem Leydig cells (SLCs) express CD51 (integrin α-chain V). However, it is still unclear whether all CD51 +  cells are SLCs. In the present study, we found that CD51 +  cells can be classified into two sub-groups, a weakly-staining group (CD51 + ) and a strongly-staining group (CD51 ++ ). The CD51 +  cells expressed common SLC marker genes, including Nestin, Pdgfra and Coup-tf2, while CD51 ++ cells did not express these genes. Instead, they expressed macrophage markers, such as F4/80, Cd115 and Tnfa. When these cells were induced to differentiate in vitro, the CD51 +  cells, but not CD51 ++ cells, formed Leydig cells. Overall, our results showed that although SLCs expressed CD51, not all CD51-expressing cells are SLCs. The cells that expressed high levels of CD51 are actually macrophages., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Bisphenol A (BPA) is widely used in consumer products and is a potential endocrine disruptor linked with abnormal development of male reproductive tract. However, its action and its effects on the pathways in the development of male gonad are still unclear. Here we report that effects of BPA exposure during gestation on male gonad development. Sprague-Dawley rats were gavaged daily with BPA (0, 4, 40, and 400 mg/kg body weight) from gestational day 12 to day 21. BPA dose-dependently decreased serum testosterone levels (0.45 ± 0.08 ng/ml and 0.32 ± 0.08 ng/ml for 40 and 400 mg/kg BPA, respectively) versus the control level (1.11 ± 0.22 ng/ml, Mean ± SE). BPA lowered Leydig cell Insl3 and Hsd17b3 mRNA and their protein levels at doses of 40 and 400 mg/kg. BPA also lowered Leydig cell (Lhcgr, Cyp11a1, and Cyp17a1) and Sertoli cell (Amh) mRNA and their protein levels at 400 mg/kg. BPA decreased fetal Leydig cell number via inhibiting their proliferation, but it did not affect fetal Sertoli cell number. In conclusion, the current study shows that in utero exposure to BPA inhibits fetal Leydig and Sertoli cell differentiation, possibly disrupting the development of male reproductive tract., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Dicyclohexyl phthalate (DCHP) is a phthalate plasticizer with a ring structure in the alcohol moiety. The objective to the current study was to determine the effects of DCHP on Leydig cell regeneration in the adult rat-testis. Adult male Sprague Dawley rats received intraperitoneally an injection of ethane dimethane sulfone (EDS) to eliminate all Leydig cells in the testis and then were divided into 4 groups of 0 (control), 10, 100, and 1000 mg/kg/day DCHP. Rats were gavaged either vehicle (corn oil, control) or DCHP from post-EDS day 7 to day 21 and 28. On post-EDS day 21 and day 28, rats were euthanized and serum testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) levels were measured, and Leydig cell number, cell size, gene, and protein expression were evaluated. During the course of exposure, DCHP did not cause the general toxicity to rats. On post-EDS day 21, DCHP significantly increased serum testosterone level at 10 and 100 mg/kg and increased Leydig cell number at 10 mg/kg via stimulating their mitosis. On post-EDS day 28, DCHP lowered serum testosterone levels and Leydig cell number at 1000 mg/kg. DCHP dose-dependently down-regulated the expression of many Leydig cell genes (Lhcgr, Scarb1, Star, Cyp11a1, Hsd3b1, Cyp17a1, Hsd17b3, Hsd11b1, and Insl3) and their proteins, especially at 1000 mg/kg. DCHP also lowered the pAKT1/AKT1 and pERK1/2/ERK1/2 ratios. In conclusion, DCHP at low doses (10 and 100 mg/kg) increased Leydig cell number during the initial regeneration and inhibited Leydig cell regeneration during the course of its exposure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Peritubular stem Leydig cells (SLCs) have been identified from rat testicular seminiferous tubules. However, no stem cells for peritubular myoid cells have been reported in the adult testis so far. In the present study, we tested the hypothesis that the peritubular SLCs are multipotent and able to form either Leydig or myoid cells. Using cultured tubules, we show that in the presence of PDGFAA and luteinizing hormone, SLCs became testosterone-producing Leydig cells, while in the presence of PDGFBB and TGFB, the cells formed α-smooth muscle actin-expressing myoid cells. This multipotency was also confirmed by culture of isolated CD90+ SLCs. These results suggest that these stem cells outside the myoid layer are multipotent and give rise to either Leydig or myoid cells, depending on the inducing factors. These cells may serve as a common precursor population for maintaining homeostasis of both Leydig and myoid cell populations in the adult testis. Image 1 • PDGFAA and PDGFBB stimulate peritubular stem cell proliferation. • PDGFAA stimulates differentiation of peritubular stem cells into Leydig cells. • PDGFBB stimulates differentiation of peritubular stem cells into myoid cells. • Isolated peritubular CD90+ cells can form either Leydig or myoid lineages in vitro. [ABSTRACT FROM AUTHOR]