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Expert Review of Molecular Diagnostics Jun 2021Sertoli cells play central roles in the development of testis formation in fetuses and the initiation and maintenance of spermatogenesis in puberty and adulthood, and... (Review)
Review
INTRODUCTION
Sertoli cells play central roles in the development of testis formation in fetuses and the initiation and maintenance of spermatogenesis in puberty and adulthood, and disorders of Sertoli cell proliferation and/or functional maturation can cause male reproductive disorders at various life stages. It's well documented that various genes are either overexpressed or absent in Sertoli cells during the conversion of an immature, proliferating Sertoli cell to a mature, non-proliferating Sertoli cell, which are considered as Sertoli cell stage-specific markers. Thus, it is paramount to choose an appropriate Sertoli cell marker that will be used not only to identify the developmental, proliferative, and maturation of Sertoli cell status in the testis during the fetal period, prepuberty, puberty, or in the adult, but also to diagnose the mechanisms underlying spermatogenic dysfunction.
AREAS COVERED
In this review, we principally enumerated 5 categories of testicular Sertoli cell markers - including immature Sertoli cell markers, mature Sertoli cell markers, immature/mature Sertoli cell markers, Sertoli cell functional markers, and others.
EXPERT OPINION
By delineating the characteristics and applications of more than 20 Sertoli cell markers, this review provided novel Sertoli cell markers for the more accurate diagnosis and mechanistic evaluation of male reproductive disorders.
Topics: Adult; Biomarkers; Humans; Male; Sertoli Cells; Spermatogenesis; Testis
PubMed: 33945376
DOI: 10.1080/14737159.2021.1924060 -
Seminars in Cell & Developmental Biology Jan 2022Sertoli cells are the orchestrators of spermatogenesis; they support fetal germ cell commitment to the male pathway and are essential for germ cell development, from... (Review)
Review
Sertoli cells are the orchestrators of spermatogenesis; they support fetal germ cell commitment to the male pathway and are essential for germ cell development, from maintenance of the spermatogonial stem cell niche and spermatogonial populations, through meiosis and spermiogeneis and to the final release of mature spermatids during spermiation. However, Sertoli cells are also emerging as key regulators of other testis somatic cells, including supporting peritubular myoid cell development in the pre-pubertal testis and supporting the function of the testicular vasculature and in contributing to testicular immune privilege. Sertoli cells also have a major role in regulating androgen production within the testis, by specifying interstitial cells to a steroidogenic fate, contributing to androgen production in the fetal testis, and supporting fetal and adult Leydig cell development and function. Here, we provide an overview of the specific roles for Sertoli cells in the testis and highlight how these cells are key drivers of testicular sperm output, and of adult testis size and optimal function of other testicular somatic cells, including the steroidogenic Leydig cells.
Topics: Animals; Humans; Leydig Cells; Male; Rats; Sertoli Cells; Testis
PubMed: 34229950
DOI: 10.1016/j.semcdb.2021.06.016 -
Developmental Cell Sep 2018Spermatogenesis requires intricate interactions between the germline and somatic cells. Within a given cross section of a seminiferous tubule, multiple germ and somatic...
Spermatogenesis requires intricate interactions between the germline and somatic cells. Within a given cross section of a seminiferous tubule, multiple germ and somatic cell types co-occur. This cellular heterogeneity has made it difficult to profile distinct cell types at different stages of development. To address this challenge, we collected single-cell RNA sequencing data from ∼35,000 cells from the adult mouse testis and identified all known germ and somatic cells, as well as two unexpected somatic cell types. Our analysis revealed a continuous developmental trajectory of germ cells from spermatogonia to spermatids and identified candidate transcriptional regulators at several transition points during differentiation. Focused analyses delineated four subtypes of spermatogonia and nine subtypes of Sertoli cells; the latter linked to histologically defined developmental stages over the seminiferous epithelial cycle. Overall, this high-resolution cellular atlas represents a community resource and foundation of knowledge to study germ cell development and in vivo gametogenesis.
Topics: Animals; Cell Differentiation; Cells, Cultured; Gene Expression Profiling; Gene Expression Regulation, Developmental; High-Throughput Nucleotide Sequencing; Male; Mice; Sertoli Cells; Single-Cell Analysis; Spermatogenesis; Testis
PubMed: 30146481
DOI: 10.1016/j.devcel.2018.07.025 -
Nature Communications Nov 2020Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA...
Clinical efficacy of treatments against non-obstructive azoospermia (NOA), which affects 1% of men, are currently limited by the incomplete understanding of NOA pathogenesis and normal spermatogenic microenvironment. Here, we profile >80,000 human testicular single-cell transcriptomes from 10 healthy donors spanning the range from infant to adult and 7 NOA patients. We show that Sertoli cells, which form the scaffold in the testicular microenvironment, are severely damaged in NOA patients and identify the roadmap of Sertoli cell maturation. Notably, Sertoli cells of patients with congenital causes (Klinefelter syndrome and Y chromosome microdeletions) are mature, but exhibit abnormal immune responses, while the cells in idiopathic NOA (iNOA) are physiologically immature. Furthermore, we find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from iNOA patients, allowing these cells to regain their ability to support germ cell survival. We provide a novel perspective on the development of diagnostic methods and therapeutic targets for NOA.
Topics: Adult; Azoospermia; Gene Expression Profiling; Humans; Male; Sertoli Cells; Single-Cell Analysis; Spermatogenesis; Spermatozoa; Testis
PubMed: 33173058
DOI: 10.1038/s41467-020-19414-4 -
Cellular and Molecular Life Sciences :... Jul 2019Spermatogenesis is fundamental to the establishment and maintenance of male reproduction, whereas its abnormality results in male infertility. Somatic cells, including... (Review)
Review
Spermatogenesis is fundamental to the establishment and maintenance of male reproduction, whereas its abnormality results in male infertility. Somatic cells, including Leydig cells, myoid cells, and Sertoli cells, constitute the microenvironment or the niche of testis, which is essential for regulating normal spermatogenesis. Leydig cells are an important component of the testicular stroma, while peritubular myoid cells are one of the major cell types of seminiferous tubules. Here we addressed the roles and mechanisms of Leydig cells and myoid cells in the regulation of spermatogenesis. Specifically, we summarized the biological features of Leydig cells and peritubular myoid cells, and we introduced the process of testosterone production and its major regulation. We also discussed other hormones, cytokines, growth factors, transcription factors and receptors associated with Leydig cells and myoid cells in mediating spermatogenesis. Furthermore, we highlighted the issues that are worthy of further studies in the regulation of spermatogenesis by Leydig cells and peritubular myoid cells. This review would provide novel insights into molecular mechanisms of the somatic cells in controlling spermatogenesis, and it could offer new targets for developing therapeutic approaches of male infertility.
Topics: Humans; Infertility, Male; Leydig Cells; Male; Seminiferous Tubules; Sertoli Cells; Spermatogenesis
PubMed: 30980107
DOI: 10.1007/s00018-019-03101-9 -
Ecotoxicology and Environmental Safety Jun 2022Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM on Sertoli cells using the TM4 cell line and...
Analysis by transcriptomics and metabolomics for the proliferation inhibition and dysfunction through redox imbalance-mediated DNA damage response and ferroptosis in male reproduction of mice and TM4 Sertoli cells exposed to PM.
Sertoli cells play a pivotal role in the complex spermatogenesis process. This study aimed to investigate the effects of PM on Sertoli cells using the TM4 cell line and a real time whole-body PM exposure mouse model, and further explore the underlying mechanisms through the application of metabolomics and transcriptomics. The results in vivo and in vitro showed that PM reduced Sertoli cells number in seminiferous tubules and inhibited cell proliferation. PM exposure also induced Sertoli cell dysfunction by increasing androgen binding protein (ABP) concentration, reducing the blood-testis barrier (BTB)-related protein expression, and decreasing glycolysis capacity and lactate production. The results of transcriptomics, metabolomics, and integrative analysis of multi-omics in the TM4 Sertoli cells revealed the activation of xenobiotic metabolism, and the disturbance of glutathione and purine metabolism after PM exposure. Further tests verified the reduced GSH/GSSG ratio and the elevation of xanthine oxidase (XO) activity in the PM-exposed TM4 cells, indicating that excessive reactive oxygen species (ROS) was generated via metabolic disorder caused by PM. Moreover, the redox imbalance was proved by the increase in the mitochondrial ROS level, superoxide dismutase (SOD) and catalase (CAT) activity, as well as the activation of the Nrf2 antioxidative pathway. Further study found that the redox imbalance caused by PM induced DNA damage response and cell cycle arrest. Additionally, PM induced ferroptosis through iron overload and lipid peroxidation. Taken all together, our study provided new insights for understanding proliferation inhibition and dysfunction of TM4 Sertoli cells exposed to PM via metabolic disorder and redox imbalance-mediated DNA damage response and ferroptosis.
Topics: Animals; Antioxidants; Apoptosis; Cell Proliferation; DNA Damage; Ferroptosis; Glutathione; Male; Metabolomics; Oxidation-Reduction; Particulate Matter; Reactive Oxygen Species; Reproduction; Sertoli Cells; Transcriptome
PubMed: 35512470
DOI: 10.1016/j.ecoenv.2022.113569 -
Protein & Cell Dec 2023The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying...
The testis is pivotal for male reproduction, and its progressive functional decline in aging is associated with infertility. However, the regulatory mechanism underlying primate testicular aging remains largely elusive. Here, we resolve the aging-related cellular and molecular alterations of primate testicular aging by establishing a single-nucleus transcriptomic atlas. Gene-expression patterns along the spermatogenesis trajectory revealed molecular programs associated with attrition of spermatogonial stem cell reservoir, disturbed meiosis and impaired spermiogenesis along the sequential continuum. Remarkably, Sertoli cell was identified as the cell type most susceptible to aging, given its deeply perturbed age-associated transcriptional profiles. Concomitantly, downregulation of the transcription factor Wilms' Tumor 1 (WT1), essential for Sertoli cell homeostasis, was associated with accelerated cellular senescence, disrupted tight junctions, and a compromised cell identity signature, which altogether may help create a hostile microenvironment for spermatogenesis. Collectively, our study depicts in-depth transcriptomic traits of non-human primate (NHP) testicular aging at single-cell resolution, providing potential diagnostic biomarkers and targets for therapeutic interventions against testicular aging and age-related male reproductive diseases.
Topics: Animals; Male; Testis; Sertoli Cells; Transcriptome; Spermatogenesis; Primates; Aging; Stem Cells
PubMed: 36929025
DOI: 10.1093/procel/pwac057 -
Frontiers in Endocrinology 2022Male germ cell development depends on multiple biological events that combine epigenetic reprogramming, cell cycle regulation, and cell migration in a spatio-temporal... (Review)
Review
Male germ cell development depends on multiple biological events that combine epigenetic reprogramming, cell cycle regulation, and cell migration in a spatio-temporal manner. Sertoli cells are a crucial component of the spermatogonial stem cell niche and provide essential growth factors and chemokines to developing germ cells. This review focuses mainly on the activation of master regulators of the niche in Sertoli cells and their targets, as well as on novel molecular mechanisms underlying the regulation of growth and differentiation factors such as GDNF and retinoic acid by NOTCH signaling and other pathways.
Topics: Cell Communication; Cell Differentiation; Humans; Male; Sertoli Cells; Spermatogonia; Stem Cell Niche
PubMed: 35757413
DOI: 10.3389/fendo.2022.897062 -
Seminars in Cell & Developmental Biology Sep 2018Cell polarity in the adult mammalian testis refers to the polarized alignment of developing spermatids during spermiogenesis and the polarized organization of organelles... (Review)
Review
Cell polarity in the adult mammalian testis refers to the polarized alignment of developing spermatids during spermiogenesis and the polarized organization of organelles (e.g., phagosomes, endocytic vesicles, Sertoli cell nuclei, Golgi apparatus) in Sertoli cells and germ cells to support spermatogenesis. Without these distinctive features of cell polarity in the seminiferous epithelium, it is not possible to support the daily production of millions of sperm in the limited space provided by the seminiferous tubules in either rodent or human males through the adulthood. In short, cell polarity provides a novel mean to align spermatids and the supporting organelles (e.g., phagosomes, Golgi apparatus, endocytic vesicles) in a highly organized fashion spatially in the seminiferous epithelium during the epithelial cycle of spermatogenesis. This is analogous to different assembling units in a manufacturing plant such that as developing spermatids move along the "assembly line" conferred by Sertoli cells, different structural/functional components can be added to (or removed from) the developing spermatids during spermiogenesis, so that functional spermatozoa are produced at the end of the assembly line. Herein, we briefly review findings regarding the regulation of cell polarity in the testis with specific emphasis on developing spermatids, supported by an intriguing network of regulatory proteins along a local functional axis. Emerging evidence has suggested that cell cytoskeletons provide the tracks which in turn confer the unique assembly lines in the seminiferous epithelium. We also provide some thought-provoking concepts based on which functional experiments can be designed in future studies.
Topics: Animals; Cell Polarity; Cytoskeleton; Humans; Male; Microtubules; Sertoli Cells; Spermatids; Spermatogenesis; Testis
PubMed: 28965865
DOI: 10.1016/j.semcdb.2017.09.037 -
Andrology May 2018Sertoli cells are located in the testes where they control several key functions in spermatogenesis. Over the past 30 years, Sertoli cells have been upgraded from a... (Review)
Review
Sertoli cells are located in the testes where they control several key functions in spermatogenesis. Over the past 30 years, Sertoli cells have been upgraded from a simple scaffold-like structural system to a dynamic functional system of intercellular support that delivers potent immunomodulatory and trophic factors. Since the discovery of new Sertoli cell secretory products, these cells have been utilized in experimental cell transplantation and co-transplantation protocols aimed at treating both chronic inflammatory and degenerative disorders. For these reasons, this work reviews the application of both naked and microencapsulated Sertoli cells used in cell transplantation studies of several chronic or autoimmune diseases such as diabetes mellitus, Laron dwarfism, and Duchenne muscular dystrophy and in studies aimed at the prevention of skin allograft rejection.
Topics: Animals; Humans; Male; Sertoli Cells
PubMed: 29600532
DOI: 10.1111/andr.12484