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Frontiers in Endocrinology 2022Since their initial description by Enrico Sertoli in 1865, Sertoli cells have continued to enchant testis biologists. Testis size and germ cell carrying capacity are... (Review)
Review
Since their initial description by Enrico Sertoli in 1865, Sertoli cells have continued to enchant testis biologists. Testis size and germ cell carrying capacity are intimately tied to Sertoli cell number and function. One critical Sertoli cell function is signaling from Sertoli cells to germ cells as part of regulation of the spermatogenic cycle. Sertoli cell signals can be endocrine or paracrine in nature. Here we review recent advances in understanding the interplay of Sertoli cell endocrine and paracrine signals that regulate germ cell state. Although these findings have long-term implications for treating male infertility, recent breakthroughs in Sertoli cell transplantation have more immediate implications. We summarize the surge of advances in Sertoli cell ablation and transplantation, both of which are wedded to a growing understanding of the unique Sertoli cell niche in the transitional zone of the testis.
Topics: Humans; Infertility, Male; Male; Sertoli Cells; Signal Transduction; Spermatogenesis; Testis
PubMed: 35600584
DOI: 10.3389/fendo.2022.897196 -
Andrology May 2021The direct correlation between Sertoli cell number and sperm production capacity highlights the importance of deciphering external factors that modify Sertoli cell...
BACKGROUND
The direct correlation between Sertoli cell number and sperm production capacity highlights the importance of deciphering external factors that modify Sertoli cell proliferation. A growing body of evidence in vitro suggests that metformin, the main pharmacological agent for type 2 diabetes treatment in children, exerts anti-proliferative effects on Sertoli cells.
OBJECTIVE
The aims of this study were to investigate the effect of metformin administration during postnatal period on Sertoli cell proliferation and on cell cycle regulators expression and to analyze the impact of this treatment on the sperm production capacity in adulthood.
MATERIALS AND METHODS
Sprague Dawley rat pups were randomly divided into two groups: MET (receiving daily 200 mg/kg metformin, from Pnd3 to Pnd7 inclusive) and control (receiving vehicle). BrdU incorporation was measured to assess proliferation. Gene expression analyses were performed in Sertoli cells isolated from animals of both groups. Daily sperm production and sperm parameters were measured in adult male rats (Pnd90) that received neonatal treatment.
RESULTS
MET group exhibited a significant decrease in BrdU incorporation in Sertoli cells. Concordantly, MET group showed a reduction in cyclin D1 and E2 expression and an increase in p21 expression in Sertoli cells. In addition, metformin-treated animals displayed lower values of daily sperm production on Pnd90.
DISCUSSION AND CONCLUSION
These results suggest that metformin treatment may lead to a decrease in Sertoli cell proliferation, a concomitant altered expression of cell cycle regulators and ultimately, a reduction in daily sperm production in adult animals.
Topics: Animals; Animals, Newborn; Cell Proliferation; Drug Evaluation, Preclinical; Female; Hypoglycemic Agents; Male; Metformin; Pregnancy; Rats, Sprague-Dawley; Sertoli Cells; Spermatogenesis; Rats
PubMed: 33305512
DOI: 10.1111/andr.12957 -
Yi Chuan = Hereditas Sep 2018Spermatogenesis requires both germ cells and testicular somatic cells, which are also involved in testicular development and male fertility. Sertoli cells are the only... (Review)
Review
Spermatogenesis requires both germ cells and testicular somatic cells, which are also involved in testicular development and male fertility. Sertoli cells are the only somatic cells in the seminiferous tubules and play very important roles in normal spermatogenesis. Abnormality of Sertoli cells in proliferation and adhesion may induce aberrant spermatogenesis and eventually cause infertility. Recently, various studies have demonstrated that miRNA are involved in the regulation of Sertoli cell proliferation and adhesion. Additionally, miRNA expression could be affected by hormone, endocrine interferon, and nutrition. In this review, we summarize miRNAs related to Sertoli cell proliferation and adhesion, which will be helpful for finding and identifying more miRNAs from Sertoli cells. The review will also provide theoretical basis for the pathogenesis of infertility associated with Sertoli cells.
Topics: Animals; Cell Proliferation; Gene Expression Regulation, Developmental; Humans; Male; MicroRNAs; Seminiferous Tubules; Sertoli Cells; Spermatogenesis
PubMed: 30369476
DOI: 10.16288/j.yczz.18-050 -
Reproduction (Cambridge, England) Mar 2019Sertoli cells regulate male germ cell proliferation and differentiation and are a critical component of the spermatogonial stem cell (SSC) niche, where homeostasis is... (Review)
Review
Sertoli cells regulate male germ cell proliferation and differentiation and are a critical component of the spermatogonial stem cell (SSC) niche, where homeostasis is maintained by the interplay of several signaling pathways and growth factors. These factors are secreted by Sertoli cells located within the seminiferous epithelium, and by interstitial cells residing between the seminiferous tubules. Sertoli cells and peritubular myoid cells produce glial cell line-derived neurotrophic factor (GDNF), which binds to the RET/GFRA1 receptor complex at the surface of undifferentiated spermatogonia. GDNF is known for its ability to drive SSC self-renewal and proliferation of their direct cell progeny. Even though the effects of GDNF are well studied, our understanding of the regulation its expression is still limited. The purpose of this review is to discuss how GDNF expression in Sertoli cells is modulated within the niche, and how these mechanisms impact germ cell homeostasis.
Topics: Animals; Cell Differentiation; Cell Self Renewal; Glial Cell Line-Derived Neurotrophic Factor; Humans; Male; Sertoli Cells; Spermatogonia; Stem Cell Niche; Stem Cells
PubMed: 30620720
DOI: 10.1530/REP-18-0239 -
Frontiers in Endocrinology 2023Sertoli cells play essential roles in male reproduction, from supporting fetal testis development to nurturing male germ cells from fetal life to adulthood.... (Review)
Review
Sertoli cells play essential roles in male reproduction, from supporting fetal testis development to nurturing male germ cells from fetal life to adulthood. Dysregulating Sertoli cell functions can have lifelong adverse effects by jeopardizing early processes such as testis organogenesis, and long-lasting processes such as spermatogenesis. Exposure to endocrine disrupting chemicals (EDCs) is recognized as contributing to the rising incidence of male reproductive disorders and decreasing sperm counts and quality in humans. Some drugs also act as endocrine disruptors by exerting off-target effects on endocrine tissues. However, the mechanisms of toxicity of these compounds on male reproduction at doses compatible with human exposure are still not fully resolved, especially in the case of mixtures, which remain understudied. This review presents first an overview of the mechanisms regulating Sertoli cell development, maintenance, and functions, and then surveys what is known on the impact of EDCs and drugs on immature Sertoli cells, including individual compounds and mixtures, and pinpointing at knowledge gaps. Performing more studies on the impact of mixtures of EDCs and drugs at all ages is crucial to fully understand the adverse outcomes these chemicals may induce on the reproductive system.
Topics: Male; Humans; Sertoli Cells; Endocrine Disruptors; Semen; Testis; Pharmaceutical Preparations
PubMed: 36793282
DOI: 10.3389/fendo.2023.1095894 -
Biology of Reproduction Nov 2022TAR DNA binding protein of 43 kD (TDP-43) is an evolutionarily conserved, ubiquitously expressed transcription factor and RNA-binding protein with major human health...
TAR DNA binding protein of 43 kD (TDP-43) is an evolutionarily conserved, ubiquitously expressed transcription factor and RNA-binding protein with major human health relevance. TDP-43 is present in Sertoli and germ cells of the testis and is aberrantly expressed in the sperm of infertile men. Sertoli cells play a key role in spermatogenesis by offering physical and nutritional support to male germ cells. The current study investigated the requirement of TDP-43 in Sertoli cells. Conditional knockout (cKO) of TDP-43 in mouse Sertoli cells caused failure of spermatogenesis and male subfertility. The cKO mice showed decreased testis weight, and low sperm count. Testis showed loss of germ cell layers, presence of vacuoles, and sloughing of round spermatids, suggesting loss of contact with Sertoli cells. Using a biotin tracer, we found that the blood-testis barrier (BTB) was disrupted as early as postnatal day 24 and worsened in adult cKO mice. We noted aberrant expression of the junction proteins connexin-43 (gap junction) and N-cadherin (ectoplasmic specialization). Oil Red O staining showed a decrease in lipid droplets (phagocytic function) in tubule cross-sections, Sertoli cells cytoplasm, and in the lumen of seminiferous tubules of cKO mice. Finally, qRT-PCR showed upregulation of genes involved in the formation and/or maintenance of Sertoli cell junctions as well as in the phagocytic pathway. Sertoli cells require TDP-43 for germ cell attachment, formation and maintenance of BTB, and phagocytic function, thus indicating an essential role for TDP-43 in the maintenance of spermatogenesis.
Topics: Animals; Male; Mice; Blood-Testis Barrier; DNA-Binding Proteins; Semen; Sertoli Cells; Spermatids; Spermatogenesis; Testis
PubMed: 35986894
DOI: 10.1093/biolre/ioac165 -
Environmental Toxicology Jan 2022Benzophenone-3 (BP-3), one of the most commonly utilized ultraviolet filters in personal care products, has aroused public concern in recent years for its high chances...
Benzophenone-3 (BP-3), one of the most commonly utilized ultraviolet filters in personal care products, has aroused public concern in recent years for its high chances of human exposure. Previous studies have found that BP-3 can impair testes development and spermatogenesis, but the targets of BP-3 are still unknown. In this study, primary Sertoli cells from 20-day-old mice were treated in vitro with 0-100 μM BP-3 for 24 h to identify its toxicity on Sertoli cells and Sertoli cell barrier. Results demonstrated that BP-3 could induce a notable change in cell morphology and impair Sertoli cell viability. The analysis of transepithelial electrical resistance showed that the integrity of the Sertoli cell barrier was destroyed by BP-3 (100 μM). Some structural proteins of the barrier including ZO-1, Occludin, and Connexin43 were lower expressed and the localization of basal ectoplasmic specializations protein β-catenin was altered because of BP-3 treatment. Further exploration suggested that BP-3 led to Sertoli cell F-actin disorganization by affecting the expression of Rictor, a key component of the mTORC2 complex. Moreover, although increased DNA damage marker γH2A.X was observed in the treatment group, the cell apoptosis rate was changeless which was further confirmed by increased BAX and stable Bcl-2 (two primary apoptosis regulating proteins). In conclusion, this study revealed that BP-3 had the potential to perturb the Sertoli cell barrier through altered junction proteins and disorganized F-actin, but it could hardly evoke Sertoli cell apoptosis.
Topics: Actins; Animals; Apoptosis; Benzophenones; Blood-Testis Barrier; Male; Mice; Rats; Rats, Sprague-Dawley; Sertoli Cells; Spermatogenesis; Tight Junctions
PubMed: 34558770
DOI: 10.1002/tox.23375 -
Trends in Cell Biology Apr 2018Specialized phagocytes are a newly appreciated classification of phagocyte that currently encompasses Sertoli cells (SCs) of the testes and the retinal pigment... (Review)
Review
Specialized phagocytes are a newly appreciated classification of phagocyte that currently encompasses Sertoli cells (SCs) of the testes and the retinal pigment epithelial cells (RPE) of the retina. While these cells support very different tissues, they have a striking degree of similarity both as phagocytes and in ways that go beyond cell clearance. The clearance of apoptotic germ cells, cell debris, and used photoreceptor outer segments are critical functions of these cells, and the unique nature of their clearance events make specialized phagocytes uniquely suited for studying the larger implications of cell clearance in vivo. The shared functions of specialized phagocytes could provide novel insights into how phagocytosis impacts tissue homeostasis and immune modulation. In this review, we examine the remarkable similarities between SCs and RPE as specialized phagocytes and the physiological effects of cell clearance within a tissue.
Topics: Animals; Homeostasis; Humans; Male; Phagocytes; Phagocytosis; Retina; Retinal Pigment Epithelium; Sertoli Cells; Testis
PubMed: 29454661
DOI: 10.1016/j.tcb.2018.01.004 -
Endocrinology Apr 2023Environmental toxicants, such as cadmium, found in foods, water, and consumer products are known to induce male reproductive dysfunction. However, the underlying...
Environmental toxicants, such as cadmium, found in foods, water, and consumer products are known to induce male reproductive dysfunction. However, the underlying molecular mechanism(s) by which cadmium-induced Sertoli cell injury as manifested by a disruption of the blood-testis barrier (BTB) remains unknown. Interestingly, one of the primary targets of cadmium toxicity in the testis is the cytoskeletons of the Sertoli cells, which, in turn, impedes cell junctions in the seminiferous epithelium. In order to expand these earlier observations and to provide a roadmap for future studies, we embarked a study using RNA sequencing to identify the pertinent genes involved in cadmium-induced Sertoli cell injury. Using bioinformatics analyses, multiple gene sets that regulated actin and microtubule (MT) cytoskeletons were identified along with components of the mitogen-activated protein kinase (MAPK) signaling protein and several signaling pathways. More important, we have also discovered that while the gene expression of p38-MAPK (also JNK or c-Jun) was considerably up- or downregulated during cadmium-induced Sertoli cell injury, the activated (phosphorylated) form was upregulated. Importantly, doramapimod (also known as BIRB 796), a specific p38-MARK inhibitor, that was shown to selectively block cadmium-induced p-p38 MAPK activation via phosphorylation in Sertoli cells, was indeed capable of blocking cadmium-induced Sertoli cell injury including disruption of the Sertoli cell-permeability barrier function, disruptive distribution of BTB-associated proteins, and disruptive organization of the actin and MT cytoskeletons. These data provide a helpful source of information for investigators to probe the role of signaling proteins and/or their signaling cascades, besides MAPKs, that likely utilized by cadmium to induce reproductive dysfunction.
Topics: Male; Humans; Sertoli Cells; Cadmium; p38 Mitogen-Activated Protein Kinases; Actins; Testis; Blood-Testis Barrier; Sequence Analysis, RNA; Spermatogenesis
PubMed: 36928142
DOI: 10.1210/endocr/bqad045 -
Biology of Reproduction Dec 2021Sertoli cells are a critical component of the testis environment for their role in maintaining seminiferous tubule structure, establishing the blood-testis barrier, and...
Sertoli cells are a critical component of the testis environment for their role in maintaining seminiferous tubule structure, establishing the blood-testis barrier, and nourishing maturing germ cells in a specialized niche. This study sought to uncover how Sertoli cells are regulated in the testis environment via germ cell crosstalk in the mouse. We found two major clusters of Sertoli cells as defined by their transcriptomes in Stages VII-VIII of the seminiferous epithelium and a cluster for all other stages. Additionally, we examined transcriptomes of germ cell-deficient testes and found that these existed in a state independent of either of the germ cell-sufficient clusters. Altogether, we highlight two main transcriptional states of Sertoli cells in an unperturbed testis environment, and a germ cell-deficient environment does not allow normal Sertoli cell transcriptome cycling and results in a state unique from either of those seen in Sertoli cells from a germ cell-sufficient environment.
Topics: Animals; Male; Mice; Sertoli Cells; Signal Transduction; Spermatozoa
PubMed: 34494084
DOI: 10.1093/biolre/ioab160