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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 -
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 -
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 -
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 -
Cells Mar 2021Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g.,... (Review)
Review
Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g., single-cell RNA sequencing), increasingly more regulatory genes related to spermatogenesis have been identified. In this review, we address the roles and mechanisms of novel genes in regulating the normal and abnormal spermatogenesis. Specifically, we discussed the functions and signaling pathways of key new genes in mediating the proliferation, differentiation, and apoptosis of rodent and human spermatogonial stem cells (SSCs), as well as in controlling the meiosis of spermatocytes and other germ cells. Additionally, we summarized the gene regulation in the abnormal testicular microenvironment or the niche by Sertoli cells, peritubular myoid cells, and Leydig cells. Finally, we pointed out the future directions for investigating the molecular mechanisms underlying human spermatogenesis. This review could offer novel insights into genetic regulation in the normal and abnormal spermatogenesis, and it provides new molecular targets for gene therapy of male infertility.
Topics: Apoptosis; Cell Differentiation; Gene Expression Regulation; Humans; Infertility, Male; Male; Sertoli Cells; Spermatogenesis
PubMed: 33802813
DOI: 10.3390/cells10030666 -
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 -
Genes Sep 2021As in other vertebrates, avian testes are the site of spermatogenesis and androgen production. The paired testes of birds differentiate during embryogenesis, first... (Review)
Review
As in other vertebrates, avian testes are the site of spermatogenesis and androgen production. The paired testes of birds differentiate during embryogenesis, first marked by the development of pre-Sertoli cells in the gonadal primordium and their condensation into seminiferous cords. Germ cells become enclosed in these cords and enter mitotic arrest, while steroidogenic Leydig cells subsequently differentiate around the cords. This review describes our current understanding of avian testis development at the cell biology and genetic levels. Most of this knowledge has come from studies on the chicken embryo, though other species are increasingly being examined. In chicken, testis development is governed by the Z-chromosome-linked gene, which directly or indirectly activates the male factors, , and . Recent single cell RNA-seq has defined cell lineage specification during chicken testis development, while comparative studies point to deep conservation of avian testis formation. Lastly, we identify areas of future research on the genetics of avian testis development.
Topics: Animals; Birds; Cell Differentiation; Chickens; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; Male; Sertoli Cells; Sex Determination Processes; Testis; Transcription Factors
PubMed: 34573441
DOI: 10.3390/genes12091459