-
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 -
Cell Stem Cell Feb 2020The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of...
The human testis undergoes dramatic developmental and structural changes during puberty, including proliferation and maturation of somatic niche cells, and the onset of spermatogenesis. To characterize this understudied process, we profiled and analyzed single-cell transcriptomes of ∼10,000 testicular cells from four boys spanning puberty and compared them to those of infants and adults. During puberty, undifferentiated spermatogonia sequentially expand and differentiate prior to the initiation of gametogenesis. Notably, we identify a common pre-pubertal progenitor for Leydig and myoid cells and delineate candidate factors controlling pubertal differentiation. Furthermore, pre-pubertal Sertoli cells exhibit two distinct transcriptional states differing in metabolic profiles before converging to an alternative single mature population during puberty. Roles for testosterone in Sertoli cell maturation, antimicrobial peptide secretion, and spermatogonial differentiation are further highlighted through single-cell analysis of testosterone-suppressed transfemale testes. Taken together, our transcriptional atlas of the developing human testis provides multiple insights into developmental changes and key factors accompanying male puberty.
Topics: Adult; Humans; Infant; Male; Puberty; Sertoli Cells; Spermatogenesis; Spermatogonia; Testis
PubMed: 31928944
DOI: 10.1016/j.stem.2019.12.005 -
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 -
Cell Stem Cell Apr 2021Human testis development in prenatal life involves complex changes in germline and somatic cell identity. To better understand, we profiled and analyzed ∼32,500...
Human testis development in prenatal life involves complex changes in germline and somatic cell identity. To better understand, we profiled and analyzed ∼32,500 single-cell transcriptomes of testicular cells from embryonic, fetal, and infant stages. Our data show that at 6-7 weeks postfertilization, as the testicular cords are established, the Sertoli and interstitial cells originate from a common heterogeneous progenitor pool, which then resolves into fetal Sertoli cells (expressing tube-forming genes) or interstitial cells (including Leydig-lineage cells expressing steroidogenesis genes). Almost 10 weeks later, beginning at 14-16 weeks postfertilization, the male primordial germ cells exit mitosis, downregulate pluripotent transcription factors, and transition into cells that strongly resemble the state 0 spermatogonia originally defined in the infant and adult testes. Therefore, we called these fetal spermatogonia "state f0." Overall, we reveal multiple insights into the coordinated and temporal development of the embryonic, fetal, and postnatal male germline together with the somatic niche.
Topics: Adult; Female; Humans; Male; Pregnancy; Sertoli Cells; Single-Cell Analysis; Spermatogonia; Stem Cells; Testis
PubMed: 33453151
DOI: 10.1016/j.stem.2020.12.004 -
Autophagy Nov 2023Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III...
Sertoli cells are highly polarized testicular cells that provide a nurturing environment for germ cell development and maturation during spermatogenesis. The class III phosphatidylinositol 3-kinase (PtdIns3K) plays core roles in macroautophagy in various cell types; however, its role in Sertoli cells remains unclear. Here, we generated a mouse line in which the gene encoding the catalytic subunit, , was specifically deleted in Sertoli cells (cKO) and found that after one round of normal spermatogenesis, the cKO mice quickly became infertile and showed disruption of Sertoli cell polarity and impaired spermiogenesis. Subsequent proteomics and phosphoproteomics analyses enriched the F-actin cytoskeleton network involved in the disorganized Sertoli-cell structure in cKO testis which we identified a significant increase of the F-actin negative regulator SCIN (scinderin) and the reduced phosphorylation of HDAC6, an α-tubulin deacetylase. Our results further demonstrated that the accumulation of SCIN in cKO Sertoli cells caused the disorder and disassembly of the F-actin cytoskeleton, which was related to the failure of SCIN degradation through the autophagy-lysosome pathway. Additionally, we found that the phosphorylation of HDAC6 at site S59 by PIK3C3 was essential for its degradation through the ubiquitin-proteasome pathway. As a result, the HDAC6 that accumulated in cKO Sertoli cells deacetylated SCIN at site K189 and led to a disorganized F-actin cytoskeleton. Taken together, our findings elucidate a new mechanism for PIK3C3 in maintaining the polarity of Sertoli cells, in which both its autophagy regulation or protein kinase activities are required for the stabilization of the actin cytoskeleton. ACTB: actin, beta; AR: androgen receptor; ATG14: autophagy related 14; BafA1: bafilomycin A; BECN1: beclin 1, autophagy related; BTB: blood-testis barrier; CASP3: caspase 3; CDC42: cell division cycle 42; CDH2: cadherin 2; CHX: cycloheximide; CTNNA1: catenin (cadherin associated protein), alpha 1; CYP11A1: cytochrome P450, family 11, subfamily A, polypeptide 1; EBSS: Earle's balanced salt solution; ES: ectoplasmic specialization; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GCNA: germ cell nuclear acidic protein; GJA1: gap junction protein, alpha 1; H2AX: H2A.X variant histone; HDAC6: histone deacetylase 6; KIT: KIT proto-oncogene, receptor tyrosine kinase; LAMP1: lysosomal associated membrane protein 1; MAP3K5: mitogen-activated protein kinase kinase kinase 5; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; OCLN: occludin; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; PNA: arachis hypogaea lectin; RAC1: Rac family small GTPase 1; SCIN: scinderin; SQSTM1/p62: sequestosome 1; SSC: spermatogonia stem cell; STK11: serine/threonine kinase 11; TJP1: tight junction protein 1; TubA: tubastatin A; TUBB3: tubulin beta 3 class III; TUNEL: TdT-mediated dUTP nick-end labeling; UB: ubiquitin; UVRAG: UV radiation resistance associated gene; VIM: vimentin; WT1: WT1 transcription factor; ZBTB16: zinc finger and BTB domain containing 16.
Topics: Male; Animals; Mice; Autophagy; Phosphorylation; Sertoli Cells; Cell Polarity; Ubiquitin; Protein Serine-Threonine Kinases; Class III Phosphatidylinositol 3-Kinases
PubMed: 37450577
DOI: 10.1080/15548627.2023.2235195 -
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 -
Journal of Controlled Release :... Oct 2023Asthenozoospermia, characterized by poor sperm motility, is a common cause of male infertility. Improving energy metabolism and alleviating oxidative stress through drug...
Asthenozoospermia, characterized by poor sperm motility, is a common cause of male infertility. Improving energy metabolism and alleviating oxidative stress through drug regimens are potential therapeutic strategies. In this study, we observed upregulated miR-24-3p levels in asthenozoospermia spermatozoa, contributing to energy metabolism disorder and oxidative stress by reducing GSK3β expression. Thus, reducing miR-24-3p levels using drugs is expected to improve sperm motility. The blood-testis barrier (BTB) protects the testis from xenobiotics and drugs. In this study, we found that Sertoli cell-derived small extracellular vesicles (SC-sEV) can traverse the BTB and enter germ cells. We successfully loaded miR-24-3p inhibitor into SC-sEV, creating the nano-drug SC-sEV@miR-24-3p inhibitor, which effectively delivers miR-24-3p inhibitor into germ cells. In a gossypol-induced mouse asthenozoospermia model, administration of SC-sEV@miR-24-3p inhibitor significantly improved sperm motility, in vitro fertilization success, and blastocyst formation rates. As anticipated, it also improved the litter size of asthenozoospermia mice. These results suggest that SC-sEV@miR-24-3p inhibitor holds promise as a potential clinical treatment for asthenospermia.
Topics: Humans; Male; Mice; Animals; Sertoli Cells; Asthenozoospermia; Sperm Motility; Blood-Testis Barrier; Semen; Spermatozoa; Germ Cells; MicroRNAs; Extracellular Vesicles
PubMed: 37595666
DOI: 10.1016/j.jconrel.2023.08.031 -
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 -
Journal of Pineal Research Oct 2022Sertoli cells (SCs) provide structural and nutritional support for developing germ cells. Normal glucose metabolism of SCs is necessary for spermatogenesis. Melatonin...
Sertoli cells (SCs) provide structural and nutritional support for developing germ cells. Normal glucose metabolism of SCs is necessary for spermatogenesis. Melatonin could alleviate the effects of heat stress on spermatogenesis. However, the influences of heat stress on glucose metabolism in SCs remain unclear, and the potential protective mechanisms of melatonin on SCs need more exploration. In this study, boar SCs were treated at 43°C for 30 min, and different concentrations of melatonin were added to protect SCs from heat stress-induced impairment. These results showed that heat stress-induced oxidative stress caused cell apoptosis, inhibited the pentose phosphate pathway, and decreased the ATP content. Furthermore, heat stress increased the expressions of glucose intake- and glycolytic-related enzymes, which enhanced the glycolysis activity to compensate for the energy deficit. Melatonin relieved heat stress-induced oxidative stress and apoptosis by activating the Kelch-like ECH-associated protein 1 (KEAP1)/NF-E2-related factor 2 signaling pathway to increase the capacity of antioxidants. In addition, melatonin enhanced heat-shock protein 90 (HSP90) expression through melatonin receptor 1B (MTNR1B), thereby stabilizing hypoxia-inducible factor-1α (HIF-1α). Activation of the HIF-1α signaling pathway enhanced glycolysis, promoted the pentose phosphate pathway, and increased cell viability. Our results suggest that melatonin reprograms glucose metabolism in SCs through the MTNR1B-HSP90-HIF-1α axis and provides a theoretical basis for preventing heat stress injury.
Topics: Animals; Glucose; HSP90 Heat-Shock Proteins; Heat-Shock Response; Kelch-Like ECH-Associated Protein 1; Male; Melatonin; NF-E2-Related Factor 2; Sertoli Cells; Swine
PubMed: 35906194
DOI: 10.1111/jpi.12819