Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation

Abstract

Sertoli cells are somatic cells present in seminiferous tubules which have essential roles in regulating spermatogenesis. Considering that each Sertoli cell is able to support a limited number of germ cells, the final number of Sertoli cells reached during the proliferative period determines sperm production capacity. Only immature Sertoli cells, which have not established the blood-testis barrier, proliferate. A number of hormonal cues regulate Sertoli cell proliferation. Among them, FSH, the insulin family of growth factors, activin, and cytokines action must be highlighted. It has been demonstrated that cAMP/PKA, ERK1/2, PI3K/Akt, and mTORC1/p70SK6 pathways are the main signal transduction pathways involved in Sertoli cell proliferation. Additionally, c-Myc and hypoxia inducible factor are transcription factors which participate in the induction by FSH of various genes of relevance in cell cycle progression. Cessation of proliferation is a pre-requisite to Sertoli cell maturation accompanied by the establishment of the blood-testis barrier. With respect to this barrier, the participation of androgens, estrogens, thyroid hormones, retinoic acid and opioids has been reported. Additionally, two central enzymes that are involved in sensing cell energy status have been associated with the suppression of Sertoli cell proliferation, namely AMPK and Sirtuin 1 (SIRT1). Among the molecular mechanisms involved in the cessation of proliferation and in the maturation of Sertoli cells, it is worth mentioning the up-regulation of the cell cycle inhibitors p21Cip1, p27Kip, and p19INK4, and of the gap junction protein connexin 43. A decrease in Sertoli cell proliferation due to administration of certain therapeutic drugs and exposure to xenobiotic agents before puberty has been experimentally demonstrated. This review focuses on the hormones, locally produced factors, signal transduction pathways, and molecular mechanisms controlling Sertoli cell proliferation and maturation. The comprehension of how the final number of Sertoli cells in adulthood is established constitutes a pre-requisite to understand the underlying causes responsible for the progressive decrease in sperm production that has been observed during the last 50 years in humans.

Production of bioactive recombinant human myeloid‐derived growth factor in Escherichia coli and its mechanism on vascular endothelial cell proliferation

“…20,23,36 In this study, the results demonstrated that our obtained protein could promote the F I G U R E 3 Mitogenic and proliferation activity analysis of different concentrations of rhMYDGF on HCAECs in vitro. 20,23,36 In this study, the results demonstrated that our obtained protein could promote the F I G U R E 3 Mitogenic and proliferation activity analysis of different concentrations of rhMYDGF on HCAECs in vitro.…”

“…It is well known that MAPK/STAT3 and PI3K signalling pathways are important for cell growth and survival. 20,23,24 Therefore, we aimed to determine whether the rhMYDGF-mediated HCAEC proliferation is associated with MAPK/STAT3 or PI3K signalling pathway. Notably, consistent with previous report, when HCAECs were treated with 100 ng/mL of rhMYDGF protein in vitro for 0, 5 and 15 minutes, respectively, the phosphorylation of MAPK1/3 and STAT3 on S727 was significantly enhanced with the time extending, while that did not occur at vehicle treatment ( Figure S6), suggesting the effect of rhMYDGF on HCAEC mitosis was closely related to the activation of MAPK1/3/STAT3 (S727), whereas rhMYDGF did not increase the phosphorylation of STAT3 on Y705 ( Figure 4A and 4), which is required for STAT3 dimerization and nuclear translocation.…”

“…Given that the MAPK/ STAT3/cyclin D1 (encoded by the human CCND1) and PI3K signalling pathways are responsible for cell proliferation, differentiation and survival, [16][17][18][19][20] we then explained the role of MAPK/STAT3, cyclin D1 and PI3K/AKT signalling pathways in rhMYDGF-mediated HCAEC proliferation. Subsequently, we tested the bioactivity and potential mechanism of rhMYDGF in HCAECs.…”

Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels

“…,30 However, opposite results on plasma IB and AMH levels during CC cannot be excluded, as T has the opposite effect on IB and AMH secretion 29,31. Meanwhile, the rise of E2 levels after CC treatment should be considered for their facilitating role in SCs proliferation 32. In contrast, during CC treatment, Overall, our data may point the possibility of damage to SCs in obese dysmetabolic men, thus supporting the hypothesis of a reduced number of SCs in obese compared with normal weight subjects 33.…”

“…However, opposite results on plasma IB and AMH levels during CC cannot be excluded, as T has the opposite effect on IB and AMH secretion . Meanwhile, the rise of E2 levels after CC treatment should be considered for their facilitating role in SCs proliferation . In contrast, during CC treatment, a parallel rise in endogenous levels of E2 and T (both about 40%) was found without altering the T/E2 ratio (pretreatment: O.16 ± 0.05 and post‐treatment 0.15 ± 0.05, P = .374) which supports the lack of damage of testicular steroidogenesis in our patients likely due to a dysfunctional hypothalamic‐pituitary‐testis axis …”