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Seminars in Cell & Developmental Biology Sep 2018It is conceivable that spermatid apico-basal polarity and spermatid planar cell polarity (PCP) are utmost important to support spermatogenesis. The orderly arrangement... (Review)
Review
It is conceivable that spermatid apico-basal polarity and spermatid planar cell polarity (PCP) are utmost important to support spermatogenesis. The orderly arrangement of developing germ cells in particular spermatids during spermiogenesis are essential to obtain structural and nutrient supports from the fixed number of Sertoli cells across the limited space of seminiferous epithelium in the tubules following Sertoli cell differentiation by ∼17 day postpartum (dpp) in rodents and ∼12 years of age at puberty in humans. Yet few studies are found in the literature to investigate the role of these proteins to support spermatogenesis. Herein, we briefly summarize recent findings in the field, in particular emerging evidence that supports the concept that apico-basal polarity and PCP are conferred by the corresponding polarity proteins through their effects on the actin- and microtubule (MT)-based cytoskeletons. While much research is needed to bridge our gaps of understanding cell polarity, cytoskeletal function, and signaling proteins, a critical evaluation of some latest findings as summarized herein provides some important and also thought-provoking concepts to design better functional experiments to address this important, yet largely expored, research topic.
Topics: Actins; Animals; Cell Polarity; Cytoskeleton; Humans; Male; Microtubules; Sertoli Cells; Spermatids; Testis
PubMed: 29410206
DOI: 10.1016/j.semcdb.2018.01.013 -
Reproduction (Cambridge, England) Jul 2021Sertoli cells proliferate and construct seminiferous tubules during fetal life, then undergo differentiation and maturation in the prepubertal testes. In the adult...
Sertoli cells proliferate and construct seminiferous tubules during fetal life, then undergo differentiation and maturation in the prepubertal testes. In the adult testes, mature Sertoli cells maintain spermatogonia and support spermatogenesis during the entire lifetime. Although Sertoli-like cells have been derived from iPS cells, they tend to remain immature. To investigate whether Sertoli cells can spontaneously acquire the ability to support spermatogenesis when transferred into the adult testis, we transplanted mouse fetal testicular cells into a Sertoli-depleted adult testis. We found that donor E12.5, E14.5 and E16.5 Sertoli cells colonized adult seminiferous tubules and supported host spermatogenesis 2 months after transplantation, demonstrating that immature fetal Sertoli cells can undergo sufficient maturation in the adult testis to become functional. This technique will be useful to analyze the developmental process of Sertoli cell maturation and to investigate the potential of iPS-derived Sertoli cells to colonize, undergo maturation, and support spermatogenesis within the testis environment.
Topics: Animals; Cell Differentiation; Female; Fetus; Male; Mice; Pregnancy; Seminiferous Tubules; Sertoli Cells; Sexual Maturation; Spermatogenesis; Testis
PubMed: 34085952
DOI: 10.1530/REP-21-0106 -
Sao Paulo Medical Journal = Revista... 2022Because normal male sexual differentiation is more complex than normal female sexual differentiation, there are more cases of disorders of sex development (DSDs) with...
BACKGROUND
Because normal male sexual differentiation is more complex than normal female sexual differentiation, there are more cases of disorders of sex development (DSDs) with 46,XY karyotype that have unclear etiology. However, Leydig and Sertoli cell markers are rarely used in distinguishing such individuals.
OBJECTIVES
To evaluate the function of Leydig and Sertoli cells in individuals with genital ambiguity, 46,XY karyotype, palpable gonads and normal testosterone secretion.
STUDY DESIGN AND SETTING
Case-control study with 77 patients, including eight with partial androgen insensitivity syndrome, eight with 5α-reductase deficiency type 2 (5ARD2) and 19 with idiopathic 46,XY DSD, and 42 healthy controls, from the Interdisciplinary Study Group for Sex Determination and Differentiation (GIEDDS), at the State University of Campinas (UNICAMP), Campinas, Brazil.
METHODS
Baseline levels of gonadotropins, anti-Müllerian hormone (AMH), inhibin B, insulin-like 3 (INSL3), testosterone and dihydrotestosterone in cases, and AMH, inhibin B, and INSL3 levels in controls, were assessed.
RESULTS
There was no significant difference in age between cases and controls (P = 0.595). AMH and inhibin B levels were significantly lower in cases than in controls (P = 0.031 and P < 0.001, respectively). INSL3 levels were significantly higher in cases than in controls (P = 0.003). Inhibin B levels were lower in 5ARD2 patients (P = 0.045) and idiopathic patients (P = 0.001), in separate comparisons with the controls.
CONCLUSION
According to our findings, we can speculate that inhibin B levels may be used to differentiate among DSD cases.
Topics: Case-Control Studies; Disorders of Sex Development; Female; Gonads; Humans; Karyotype; Male; Sertoli Cells; Testosterone
PubMed: 35137906
DOI: 10.1590/1516-3180.2021.0042.R1.08062021 -
Cells Jun 2021Timely and efficient elimination of apoptotic substrates, continuously produced during one's lifespan, is a vital need for all tissues of the body. This task is achieved... (Review)
Review
Timely and efficient elimination of apoptotic substrates, continuously produced during one's lifespan, is a vital need for all tissues of the body. This task is achieved by cells endowed with phagocytic activity. In blood-separated tissues such as the retina, the testis and the ovaries, the resident cells of epithelial origin as retinal pigmented epithelial cells (RPE), testis Sertoli cells and ovarian granulosa cells (GC) provide phagocytic cleaning of apoptotic cells and cell membranes. Disruption of this process leads to functional ablation as blindness in the retina and compromised fertility in males and females. To ensure the efficient elimination of apoptotic substrates, RPE, Sertoli cells and GC combine various mechanisms allowing maintenance of tissue homeostasis and avoiding acute inflammation, tissue disorganization and functional ablation. In tight cooperation with other phagocytosis receptors, MERTK-a member of the TAM family of receptor tyrosine kinases (RTK)-plays a pivotal role in apoptotic substrate cleaning from the retina, the testis and the ovaries through unconventional autophagy-assisted phagocytosis process LAP (LC3-associated phagocytosis). In this review, we focus on the interplay between TAM RTKs, autophagy-related proteins, LAP, and Toll-like receptors (TLR), as well as the regulatory mechanisms allowing these components to sustain tissue homeostasis and prevent functional ablation of the retina, the testis and the ovaries.
Topics: Animals; Autophagy; Female; Granulosa Cells; Humans; Male; Phagocytosis; Retina; Sertoli Cells; c-Mer Tyrosine Kinase
PubMed: 34207717
DOI: 10.3390/cells10061443 -
Ecotoxicology and Environmental Safety Mar 2023Zearalenone (ZEA), one of the non-steroidal estrogen mycotoxin, can cause male reproductive damage and genotoxicity in mammals. Testicular oxidative injury is an...
Zearalenone (ZEA), one of the non-steroidal estrogen mycotoxin, can cause male reproductive damage and genotoxicity in mammals. Testicular oxidative injury is an important factor causing male sterility. Testicular Sertoli cells are essential for spermatogenesis and male fertility. At present, the mechanism of oxidative injury in dairy goat Sertoli cells after exposure to ZEA remains unclear. This study explored the effects of ZEA on oxidative stress and autophagy in dairy goat Sertoli cells. It was found that treatment of primary Sertoli cells with 25, 50 and 100 μmol/L ZEA for 24 h can promote ROS production, decrease cell viability, antioxidant enzyme activity and mitochondrial membrane potential, induce caspase-dependent cell apoptosis and autophagy activity. ZEA-induced autophagy was confirmed by LC3-I/LC3-II transformation. More importantly, N-acetylcysteine (NAC) pretreatment can remarkably inhibit ZEA-induced oxidative stress, apoptosis and autophagy in Sertoli cells by eliminating ROS. In conclusion, this study indicates that ZEA induces oxidative stress and autophagy in dairy goat Sertoli cells by promoting ROS production.
Topics: Animals; Male; Zearalenone; Sertoli Cells; Reactive Oxygen Species; Goats; Oxidative Stress; Apoptosis; Autophagy
PubMed: 36708663
DOI: 10.1016/j.ecoenv.2023.114571 -
Medicinal Research Reviews Jan 2015Otto Warburg observed that cancerous cells prefer fermentative instead of oxidative metabolism of glucose, although the former is in theory less efficient. Since... (Review)
Review
Otto Warburg observed that cancerous cells prefer fermentative instead of oxidative metabolism of glucose, although the former is in theory less efficient. Since Warburg's pioneering works, special attention has been given to this difference in cell metabolism. The Warburg effect has been implicated in cell transformation, immortalization, and proliferation during tumorigenesis. Cancer cells display enhanced glycolytic activity, which is correlated with high proliferation, and thus, glycolysis appears to be an excellent candidate to target cancer cells. Nevertheless, little attention has been given to noncancerous cells that exhibit a "Warburg-like" metabolism with slight, but perhaps crucial, alterations that may provide new directions to develop new and effective anticancer therapies. Within the testis, the somatic Sertoli cell (SC) presents several common metabolic features analogous to cancer cells, and a clear "Warburg-like" metabolism. Nevertheless, SCs actively proliferate only during a specific time period, ceasing to divide in most species after puberty, when they become terminally differentiated. The special metabolic features of SC, as well as progression from the immature but proliferative state, to the mature nonproliferative state, where a high glycolytic activity is maintained, make these cells unique and a good model to discuss new perspectives on the Warburg effect. Herein we provide new insight on how the somatic SC may be a source of new and exciting information concerning the Warburg effect and cell proliferation.
Topics: Animals; Cell Proliferation; Glycolysis; Humans; Lactates; Male; Neoplasms; Sertoli Cells
PubMed: 25043918
DOI: 10.1002/med.21325 -
Reproduction (Cambridge, England) Oct 2021Fetal development of the mammalian testis relies on a series of interrelated cellular processes: commitment of somatic progenitor cells to Sertoli and Leydig cell fate,... (Review)
Review
Fetal development of the mammalian testis relies on a series of interrelated cellular processes: commitment of somatic progenitor cells to Sertoli and Leydig cell fate, migration of endothelial cells and Sertoli cells, differentiation of germ cells, deposition of the basement membrane, and establishment of cell-cell contacts, including Sertoli-Sertoli and Sertoli-germ cell contacts. These processes are orchestrated by intracellular, endocrine, and paracrine signaling processes. Because of this complexity, testis development can be disrupted by a variety of environmental toxicants. The toxicity of phthalic acid esters (phthalates) on the fetal testis has been the subject of extensive research for two decades, and phthalates have become an archetypal fetal testis toxicant. Phthalates disrupt the seminiferous cord formation and maturation, Sertoli cell function, biosynthesis of testosterone in Leydig cells, and impair germ cell survival and development, producing characteristic multinucleated germ cells. However, the mechanisms responsible for these effects are not fully understood. This review describes current knowledge of the adverse effects of phthalates on the fetal testis and their associated windows of sensitivity, and compares and contrasts the mechanisms by which toxicants of current interest, bisphenol A and its replacements, analgesics, and perfluorinated alkyl substances, alter testicular developmental processes. Working toward a better understanding of the molecular mechanisms responsible for phthalate toxicity will be critical for understanding the long-term impacts of environmental chemicals and pharmaceuticals on human reproductive health.
Topics: Animals; Endothelial Cells; Environmental Exposure; Fetal Development; Leydig Cells; Male; Phthalic Acids; Sertoli Cells; Testis
PubMed: 34314370
DOI: 10.1530/REP-20-0592 -
International Journal of Molecular... Jan 2023The complement system is an important component of transplant rejection. Sertoli cells, an immune regulatory testicular cell, survive long-term when transplanted across...
The complement system is an important component of transplant rejection. Sertoli cells, an immune regulatory testicular cell, survive long-term when transplanted across immunological barriers; thus, understanding the mechanisms behind this unique survival would be of great benefit to the transplantation field. This study focused on Sertoli cell inhibition of complement as relevant in xenotransplantation. Neonatal pig Sertoli cells (NPSCs) survived activated human complement in vitro while neonatal pig islet (NPI) aggregates and pig aortic endothelial cell (PAEC) survival were diminished to about 65% and 12%, respectively. PAECs cultured in NPSC-conditioned media and human complement demonstrated a 200% increase in survival suggesting that NPSCs secrete complement-inhibiting substances that confer protection. Bioinformatic and molecular analyses identified 21 complement inhibitors expressed by NPSCs with several significantly increased in NPSCs compared to NPIs or PAECs. Lastly, RNA sequencing revealed that NPSCs express 25 other complement factors including cascade components and receptors. Overall, this study identified the most comprehensive Sertoli cell complement signature to date and indicates that the expression of a variety of complement inhibitors ensures a proper regulation of complement through redundant inhibition points. Understanding the regulation of the complement system should be further investigated for extending xenograft viability.
Topics: Humans; Male; Complement Inactivating Agents; Complement System Proteins; Graft Rejection; Heterografts; Sertoli Cells; Transplantation, Heterologous; Swine; Animals
PubMed: 36768217
DOI: 10.3390/ijms24031890 -
Cells Nov 2023The transforming growth factor β (TGFβ) superfamily, consisting of protein ligands, receptors, and intracellular SMAD transducers, regulates fundamental biological...
The transforming growth factor β (TGFβ) superfamily, consisting of protein ligands, receptors, and intracellular SMAD transducers, regulates fundamental biological processes and cancer development. Our previous study has shown that sustained activation of TGFβ receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 ()-Cre in the mouse testis induces the formation of testicular granulosa cell tumors (TGCTs). As -Cre is expressed in both Sertoli cells and Leydig cells, it remains unclear whether the activation of TGFBR1 in Sertoli cells alone is sufficient to induce TGCT formation. Therefore, the objective of this study was to determine whether Sertoli cell-activation of TGFBR1 drives oncogenesis in the testis. Our hypothesis was that overactivation of TGFBR1 in Sertoli cells would promote their transdifferentiation into granulosa-like cells and the formation of TGCTs. To test this hypothesis, we generated mice harboring constitutive activation of TGFBR1 in Sertoli cells using anti-Mullerian hormone ()-Cre. Disorganized seminiferous tubules and tumor nodules were found in ; -Cre mice. A histological analysis showed that Sertoli cell-specific activation of TGFBR1 led to the development of neoplasms resembling granulosa cell tumors, which derailed spermatogenesis. Moreover, TGCTs expressed granulosa cell markers including FOXL2, FOXO1, and INHA. Using a dual fluorescence reporter line, the membrane-targeted tdTomato (mT)/membrane-targeted EGFP (mG) mouse, we provided evidence that Sertoli cells transdifferentiated toward a granulosa cell fate during tumorigenesis. Thus, our findings indicate that Sertoli cell-specific activation of TGFBR1 leads to the formation of TGCTs, supporting a key contribution of Sertoli cell reprogramming to the development of this testicular malignancy in our model.
Topics: Male; Humans; Female; Mice; Animals; Sertoli Cells; Granulosa Cell Tumor; Receptor, Transforming Growth Factor-beta Type I; Testicular Neoplasms; Receptors, Transforming Growth Factor beta; Anti-Mullerian Hormone; Transforming Growth Factor beta; Ovarian Neoplasms
PubMed: 38067144
DOI: 10.3390/cells12232717 -
Andrology Jul 2020Spermatogenesis in mammals is organized in a manner that maximizes sperm production. The central aspect of this organization is the cycle of the seminiferous epithelium... (Review)
Review
BACKGROUND
Spermatogenesis in mammals is organized in a manner that maximizes sperm production. The central aspect of this organization is the cycle of the seminiferous epithelium that is characterized by an asynchronous repeating series of germ cell associations. These cell associations are the result of a fixed point of entry into the cycle at regular short time intervals and the longer time required for cells to fully differentiate and exit the cycle.
OBJECTIVE
This review will examine the current information on the action and metabolism of retinoic acid in the testis, the interaction of retinoic acid (RA) with the cycle and the spermatogenic wave, and the mechanisms that can lead to synchronous spermatogenesis. Finally, the unique applications of synchronous spermatogenesis to the study of the cycle and the mass isolation of specific germ cell populations are described.
MATERIALS AND METHODS
Retinoic acid metabolism and spermatogonial differentiation have been examined by gene deletions, immunocytochemistry, chemical inhibitors, and mass spectrometry.
RESULTS, DISCUSSION, AND CONCLUSION
Both the Sertoli cells and the germ cells have the capacity to synthesize retinoic acid from retinol and in the mouse the entry into the cycle of the seminiferous epithelium, and the subsequent conversion of undifferentiated spermatogonia into differentiating spermatogonia is governed by a peak of RA synthesis occurring at stages VIII-IX of the cycle. Normal asynchronous spermatogenesis can be modified by altering RA levels, and as a result the entire testis will consist of a few closely related stages of the cycle.
Topics: Animals; Cell Differentiation; Humans; Male; Mice; Sertoli Cells; Spermatogenesis; Spermatogonia; Spermatozoa
PubMed: 31670467
DOI: 10.1111/andr.12722