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Molecular Reproduction and Development Aug 2020Sertoli cells play a vital role in spermatogenesis by offering physical and nutritional support to the differentiating male germ cells. They form the blood-testis... (Review)
Review
Sertoli cells play a vital role in spermatogenesis by offering physical and nutritional support to the differentiating male germ cells. They form the blood-testis barrier and secrete growth factors essential for germ cell differentiation. Sertoli cell primary cultures are critical for understanding the regulation of spermatogenesis; however, obtaining pure cultures has been a challenge. Rodent Sertoli cell isolation protocols do not rule out contamination by the interstitial or connective tissue cells. Sertoli cell-specific markers could be helpful, but there is no consensus. Vimentin, the most commonly used marker, is not specific for Sertoli cells since its expression has been reported in peritubular myoid cells, mesenchymal stem cells, fibroblasts, macrophages, and endothelial cells, which contaminate Sertoli cell preparations. Markers based on transcription and growth factors also have limitations. Thus, the impediment to obtaining pure Sertoli cell cultures pertains to both the method of isolation and marker usage. The aim of this review is to discuss improvements to current methods of rodent Sertoli cell primary cultures, assess the properties of prepubertal versus mature Sertoli cell cultures, and propose steps to improve cellular characterization. Potential benefits of using contemporary approaches, including lineage tracing, specific cell ablation, and RNA-seq for obtaining Sertoli-specific transcript markers are discussed. Evaluating the specificity and applicability of these markers at the protein level to characterize Sertoli cells in culture would be critical. This review is expected to positively impact future work using primary cultures of rodent Sertoli cells.
Topics: Animals; Cell Differentiation; Cells, Cultured; Humans; Male; Primary Cell Culture; Rodentia; Sertoli Cells; Spermatogenesis
PubMed: 32743879
DOI: 10.1002/mrd.23402 -
Andrology Nov 2015Testicular development and function is the culmination of a complex process of autocrine, paracrine and endocrine interactions between multiple cell types. Dissecting... (Review)
Review
Testicular development and function is the culmination of a complex process of autocrine, paracrine and endocrine interactions between multiple cell types. Dissecting this has classically involved the use of systemic treatments to perturb endocrine function, or more recently, transgenic models to knockout individual genes. However, targeting genes one at a time does not capture the more wide-ranging role of each cell type in its entirety. An often overlooked, but extremely powerful approach to elucidate cellular function is the use of cell ablation strategies, specifically removing one cellular population and examining the resultant impacts on development and function. Cell ablation studies reveal a more holistic overview of cell-cell interactions. This not only identifies important roles for the ablated cell type, which warrant further downstream study, but also, and importantly, reveals functions within the tissue that occur completely independently of the ablated cell type. To date, cell ablation studies in the testis have specifically removed germ cells, Leydig cells, macrophages and recently Sertoli cells. These studies have provided great leaps in understanding not possible via other approaches; as such, cell ablation represents an essential component in the researchers' tool-kit, and should be viewed as a complement to the more mainstream approaches to advancing our understanding of testis biology. In this review, we summarise the cell ablation models used in the testis, and discuss what each of these have taught us about testis development and function.
Topics: Ablation Techniques; Animals; Cell Communication; Humans; Leydig Cells; Macrophages; Male; Models, Animal; Sertoli Cells; Signal Transduction; Spermatogenesis; Spermatozoa; Testis
PubMed: 26446427
DOI: 10.1111/andr.12107 -
Hormones (Athens, Greece) 2015The Sertoli cell is important for endocrine and paracrine control of spermatogenesis. Functions attributed to Sertoli cells are: (1) supportive and trophic functions for... (Review)
Review
The Sertoli cell is important for endocrine and paracrine control of spermatogenesis. Functions attributed to Sertoli cells are: (1) supportive and trophic functions for the cells of the seminiferous epithelium, (2) transport of mature spermatids towards the lumen of seminiferous tubules, (3) secretion of androgen binding protein, (4) production of substances with endocrine or paracrine action for spermatogenesis control and (5) interaction with intertubular endocrine Leydig cells. Inhibin B and anti-Müllerian hormone (AMH) are glycoproteins belonging to the transforming growth factor β (TGF-β) superfamily; they are produced almost exclusively by the Sertoli cells and have been proposed as direct markers of their function and indirect markers of spermatogenesis. Serum inhibin B and AMH concentrations seem to constitute additional diagnostic parameters in male subfertility as they reflect Sertoli cell function. Stimulated concentrations of serum inhibin B and AMH do not add clinically relevant information in subfertile men compared to basal concentrations of these hormones. Serum inhibin B and AMH concentrations correlate with testicular histology/cytology but are not superior to FSH as predictors of the presence of sperm in testicular sperm extraction (TESE)/fine needle aspiration (FNA) biopsy in men with azoospermia.
Topics: Animals; Anti-Mullerian Hormone; Azoospermia; Biomarkers; Biopsy, Fine-Needle; Fertility; Follicle Stimulating Hormone; Humans; Inhibins; Male; Paracrine Communication; Predictive Value of Tests; Sertoli Cells; Signal Transduction; Spermatogenesis
PubMed: 26859601
DOI: 10.14310/horm.2002.1648 -
Der Pathologe Dec 2019Sertoli cells (SCs) play a central role in the development of the male genital organs and are absolutely necessary in the adult testis for the maintenance of a normal... (Review)
Review
Sertoli cells (SCs) play a central role in the development of the male genital organs and are absolutely necessary in the adult testis for the maintenance of a normal spermatogenesis. They form the blood-testis barrier, which is a physical barrier between the blood vessels and the seminiferous tubules. Tight junctions between the cell membranes of adjacent SCs divide the seminiferous tubule in a basal compartment (in contact with blood and lymph) and an adluminal compartment (isolated from blood and lymph).The SCs produce more than 60 proteins, of which the most important are hormones. The anti-Müllerian hormone inhibits the development of the female Müllerian ducts in the male embryo. Inhibin inhibits the production of follicle-stimulating hormone (FSH). Activin is an antagonist of inhibin and follistatin inhibits the effect of activin. Furthermore, diverse growth factors are produced, which have auto- and paracrine effects. Androgen-binding protein makes the androgen less lipophilic and becomes more concentrated within the luminal fluid of the seminiferous tubules thus enabling spermatogenesis. Ferritin is necessary for the transport of iron to the rapidly growing germ cells.SCs selectively and rapidly eliminate apoptotic residua of spermatids through phagocytosis. Moreover, as shown in animal experiments, these cells are also able to phagocytize and kill bacteria.Sertoli cell tumors are characterized by a broad spectrum of diversity ranging from highly differentiated adenocarcinoma-like types to completely undifferentiated spindled cell variants.
Topics: Animals; Female; Inhibins; Male; Seminiferous Tubules; Sertoli Cells; Spermatogenesis; Testis
PubMed: 31754790
DOI: 10.1007/s00292-019-00711-9 -
Trends in Molecular Medicine Sep 2018Studies have proven that per- and polyfluoroalkyl substances are harmful to humans, most notably perfluorooctanesulfonate (PFOS). PFOS induces rapid disorganization of... (Review)
Review
Studies have proven that per- and polyfluoroalkyl substances are harmful to humans, most notably perfluorooctanesulfonate (PFOS). PFOS induces rapid disorganization of actin- and microtubule (MT)-based cytoskeletons in primary cultures of rodent and human Sertoli cells, perturbing Sertoli cell gap junction communication, thereby prohibiting Sertoli cells from maintaining cellular homeostasis in the seminiferous epithelium to support spermatogenesis. PFOS perturbs several signaling proteins/pathways, such as FAK and mTORC1/rpS6/Akt1/2. The use of either an activator of Akt1/2 or overexpression of a phosphomimetic (and constitutively active) mutant of FAK or connexin 43 has demonstrated that such treatment blocks PFOS-induced Sertoli cell injury by preventing actin- and MT-based cytoskeletal disorganization. These findings thus illustrate an approach to manage PFOS-induced reproductive dysfunction.
Topics: Alkanesulfonic Acids; Animals; Environmental Pollutants; Fluorocarbons; Gap Junctions; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Proto-Oncogene Proteins c-akt; Rats; Sertoli Cells; Signal Transduction; TOR Serine-Threonine Kinases
PubMed: 30056046
DOI: 10.1016/j.molmed.2018.07.001 -
Human Reproduction (Oxford, England) Mar 2023Extracellular vesicles (EVs) are nano-sized membrane-bounded particles, released by all cells and capable of transporting bioactive cargoes, proteins, lipids, and...
Extracellular vesicles (EVs) are nano-sized membrane-bounded particles, released by all cells and capable of transporting bioactive cargoes, proteins, lipids, and nucleic acids, to regulate a variety of biological functions. Seminal plasma is enriched in EVs, and extensive evidence has revealed the role of EVs (e.g. prostasomes and epididymosomes) in the male genital tract. Recently, EVs released from testicular cells have been isolated and identified, and some new insights have been generated on their role in maintaining normal spermatogenesis and steroidogenesis in the testis. In the seminiferous tubules, Sertoli cell-derived EVs can promote the differentiation of spermatogonial stem cells (SSCs), and EVs secreted from undifferentiated A spermatogonia can inhibit the proliferation of SSCs. In the testicular interstitium, EVs have been identified in endothelial cells, macrophages, telocytes, and Leydig cells, although their roles are still elusive. Testicular EVs can also pass through the blood-testis barrier and mediate inter-compartment communication between the seminiferous tubules and the interstitium. Immature Sertoli cell-derived EVs can promote survival and suppress the steroidogenesis of Leydig cells. Exosomes isolated from macrophages can protect spermatogonia from radiation-induced injury. In addition to their role in intercellular communication, testicular EVs may also participate in the removal of aberrant proteins and the delivery of antigens for immune tolerance. EVs released from testicular cells can be detected in seminal plasma, which makes them potential biomarkers reflecting testicular function and disease status. The testicular EVs in seminal plasma may also affect the female reproductive tract to facilitate conception and may even affect early embryogenesis through modulating sperm RNA. EVs represent a new type of intercellular messenger in the testis. A detailed understanding of the role of testicular EV may contribute to the discovery of new mechanisms causing male infertility and enable the development of new diagnostic and therapeutic strategies for the treatment of infertile men.
Topics: Male; Female; Humans; Testis; Endothelial Cells; Semen; Spermatogenesis; Spermatogonia; Sertoli Cells; Infertility, Male; Extracellular Vesicles
PubMed: 36728671
DOI: 10.1093/humrep/dead015 -
Reproduction, Fertility, and Development Nov 2023Cadherins (CDH) are crucial intercellular adhesion molecules, contributing to morphogenesis and creating tissue barriers by regulating cells' movement, clustering and... (Review)
Review
Cadherins (CDH) are crucial intercellular adhesion molecules, contributing to morphogenesis and creating tissue barriers by regulating cells' movement, clustering and differentiation. In the testis, classical cadherins such as CDH1, CDH2 and CDH3 are critical to gonadogenesis by promoting the migration and the subsequent clustering of primordial germ cells with somatic cells. While CDH2 is present in both Sertoli and germ cells in rodents, CDH1 is primarily detected in undifferentiated spermatogonia. As for CDH3, its expression is mainly found in germ and pre-Sertoli cells in developing gonads until the establishment of the blood-testis barrier (BTB). This barrier is made of Sertoli cells forming intercellular junctional complexes. The restructuring of the BTB allows the movement of early spermatocytes toward the apical compartment as they differentiate during a process called spermatogenesis. CDH2 is among many junctional proteins participating in this process and is regulated by several pathways. While cytokines promote the disassembly of the BTB by enhancing junctional protein endocytosis for degradation, testosterone facilitates the assembly of the BTB by increasing the recycling of endocytosed junctional proteins. Mitogen-activated protein kinases (MAPKs) are also mediators of the BTB kinetics in many chemically induced damages in the testis. In addition to regulating Sertoli cell functions, follicle stimulating hormone can also regulate the expression of CDH2. In this review, we discuss the current knowledge on regulatory mechanisms of cadherin localisation and expression in the testis.
Topics: Male; Animals; Testis; Cadherins; Sertoli Cells; Spermatogenesis; Spermatocytes
PubMed: 37717581
DOI: 10.1071/RD23084 -
Biology of Reproduction Jun 2023Sertoli cells, first identified in the adult testis by Enrico Sertoli in the mid-nineteenth century, are known for their role in fostering male germ cell differentiation... (Review)
Review
Sertoli cells, first identified in the adult testis by Enrico Sertoli in the mid-nineteenth century, are known for their role in fostering male germ cell differentiation and production of mature sperm. It was not until the late twentieth century with the discovery of the testis-determining gene SRY that Sertoli cells' new function as the master regulator of testis formation and maleness was unveiled. Fetal Sertoli cells facilitate the establishment of seminiferous cords, induce appearance of androgen-producing Leydig cells, and cause regression of the female reproductive tracts. Originally thought be a terminally differentiated cell type, adult Sertoli cells, at least in the mouse, retain their plasticity and ability to transdifferentiate into the ovarian counterpart, granulosa cells. In this review, we capture the many phases of Sertoli cell differentiation from their fate specification in fetal life to fate maintenance in adulthood. We also introduce the discovery of a new phase of fetal Sertoli cell differentiation via autocrine/paracrine factors with the freemartin characteristics. There remains much to learn about this intriguing cell type that lay the foundation for the maleness.
Topics: Cattle; Male; Female; Animals; Mice; Testis; Freemartinism; Semen; Sertoli Cells; Leydig Cells
PubMed: 36951956
DOI: 10.1093/biolre/ioad037 -
Protein and Peptide Letters 2018Sertoli cell, over the past 30 years, have been elevated from simple mechanical elements to the rank of a "sentinel" in spermatogenesis. By delivering potent... (Review)
Review
BACKGROUND
Sertoli cell, over the past 30 years, have been elevated from simple mechanical elements to the rank of a "sentinel" in spermatogenesis. By delivering potent immunomodulatory and trophic proteins, Sertoli cells are unique cell type with a pivotal role in maintaining testis immune privilege and the immune-protection of the antigenic germ cells.
CONCLUSIONS
The findings from SC transplantation studies utilizing experimental animal models of disease, demonstrate the presence of the same immuno-modulation properties and mechanisms at tissue and organ sites far from testis. The complex pathways that generate and maintain the immune tolerance involve the production of several immunomodulatory or immune-related proteins such as cytokines, chemokines, growth factors, mediators of the inflammation, complement inhibitors or adhesion molecules. A better definition and understanding of these Sertoli cell proteins and the mechanisms of immunoprotection should help to elucidate their role in the spermatogenic process. The demonstration of their capabilities in transplantation experiments suggests that Sertoli cells may be good candidates in cell therapy for a number of cell-mediated chronic diseases.
Topics: Animals; Blood-Testis Barrier; Humans; Immune Tolerance; Male; Sertoli Cells; Spermatogenesis
PubMed: 29651939
DOI: 10.2174/0929866525666180412163151 -
Seminars in Cell & Developmental Biology Sep 2018In adult mammalian testes, spermatids, most notably step 17-19 spermatids in stage IV-VIII tubules, are aligned with their heads pointing toward the basement membrane... (Review)
Review
In adult mammalian testes, spermatids, most notably step 17-19 spermatids in stage IV-VIII tubules, are aligned with their heads pointing toward the basement membrane and their tails toward the tubule lumen. On the other hand, these polarized spermatids also align across the plane of seminiferous epithelium, mimicking planar cell polarity (PCP) found in other hair cells in cochlea (inner ear). This orderly alignment of developing spermatids during spermiogenesis is important to support spermatogenesis, such that the maximal number of developing spermatids can be packed and supported by a fixed population of differentiated Sertoli cells in the limited space of the seminiferous epithelium in adult testes. In this review, we provide emerging evidence to demonstrate spermatid PCP in the seminiferous epithelium to support spermatogenesis. We also review findings in the field regarding the biology of spermatid cellular polarity (e.g., head-tail polarity and apico-basal polarity) and its inter-relationship to spermatid PCP. Furthermore, we also provide a hypothetical concept on the importance of PCP proteins in endocytic vesicle-mediated protein trafficking events to support spermatogenesis through protein endocytosis and recycling.
Topics: Animals; Cell Polarity; Humans; Male; Sertoli Cells; Signal Transduction; Spermatids; Spermatogenesis; Testis
PubMed: 28923514
DOI: 10.1016/j.semcdb.2017.09.008