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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 -
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 -
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 -
Hormone Research 2006The somatic Sertoli cell plays an essential role in embryonic determination of male somatic sex and in spermatogenesis during adult life. One individual Sertoli cell... (Review)
Review
The somatic Sertoli cell plays an essential role in embryonic determination of male somatic sex and in spermatogenesis during adult life. One individual Sertoli cell supplies a clone of developing germ cells with nutrients and growth factors and it is well established that the number of Sertoli cells present is closely correlated to both testicular size and sperm output. Sertoli cells continue to proliferate and differentiate until the beginning of puberty, when they cease dividing and start nursing the germ cells. At this point in time, the future capacity of the testis for sperm production has thus been determined. Prior to puberty the Sertoli cells are immature and differ considerably with respect to morphology and biochemical activity from the mature cell. The several investigations that have focused on hormonal and paracrine regulation of the functions of the mature cell are reviewed here, but the mechanisms underlying the maturation and general maintenance of well-functioning Sertoli cells remain obscure. An alarming decline in male reproductive health has been observed in several Western countries during recent decades. Disturbance of Sertoli cell differentiation is thought to be involved in the pathogenesis of both a poor sperm count and testicular cancer. It is speculated that environmental agents that disrupt the estrogenic/androgenic balance in the testis may play a role in this connection.
Topics: Animals; Cell Proliferation; Endocrine System; Germ Cells; Hormones; Humans; Male; Models, Biological; Organ Size; Paracrine Communication; Sertoli Cells; Spermatozoa; Testicular Diseases; Testis
PubMed: 16804315
DOI: 10.1159/000094142 -
Reproduction (Cambridge, England) Mar 2019Sertoli cells regulate male germ cell proliferation and differentiation and are a critical component of the spermatogonial stem cell (SSC) niche, where homeostasis is... (Review)
Review
Sertoli cells regulate male germ cell proliferation and differentiation and are a critical component of the spermatogonial stem cell (SSC) niche, where homeostasis is maintained by the interplay of several signaling pathways and growth factors. These factors are secreted by Sertoli cells located within the seminiferous epithelium, and by interstitial cells residing between the seminiferous tubules. Sertoli cells and peritubular myoid cells produce glial cell line-derived neurotrophic factor (GDNF), which binds to the RET/GFRA1 receptor complex at the surface of undifferentiated spermatogonia. GDNF is known for its ability to drive SSC self-renewal and proliferation of their direct cell progeny. Even though the effects of GDNF are well studied, our understanding of the regulation its expression is still limited. The purpose of this review is to discuss how GDNF expression in Sertoli cells is modulated within the niche, and how these mechanisms impact germ cell homeostasis.
Topics: Animals; Cell Differentiation; Cell Self Renewal; Glial Cell Line-Derived Neurotrophic Factor; Humans; Male; Sertoli Cells; Spermatogonia; Stem Cell Niche; Stem Cells
PubMed: 30620720
DOI: 10.1530/REP-18-0239 -
Seminars in Cell & Developmental Biology Jun 2014Testicular germ cells, which appear after the establishment of central tolerance, express novel cell surface and intracellular proteins that can be recognized as... (Review)
Review
Testicular germ cells, which appear after the establishment of central tolerance, express novel cell surface and intracellular proteins that can be recognized as 'foreign antigens' by the host's immune system. However, normally these germ cells do not evoke an auto-reactive immune response. The focus of this manuscript is to review the evidence that the blood-testis-barrier (BTB)/Sertoli cell (SC) barrier along with the SCs ability to modulate the immune response is vital for protecting auto-antigenic germ cells. In normal testis, the BTB/SC barrier protects the majority of the auto-antigenic germ cells by limiting access by the immune system and sequestering these 'new antigens'. SCs also modulate testis immune cells (induce regulatory immune cells) by expressing several immunoregulatory factors, thereby creating a local tolerogenic environment optimal for survival of nonsequesetred auto-antigenic germ cells. Collectively, the fortress created by the BTB/SC barrier along with modulation of the immune response is pivotal for completion of spermatogenesis and species survival.
Topics: Animals; Autoantigens; Autoimmunity; Blood-Testis Barrier; Humans; Male; Peripheral Tolerance; Sertoli Cells; Spermatogenesis; Spermatozoa; Testis
PubMed: 24603046
DOI: 10.1016/j.semcdb.2014.02.011 -
Biology of Reproduction Nov 2022TAR DNA binding protein of 43 kD (TDP-43) is an evolutionarily conserved, ubiquitously expressed transcription factor and RNA-binding protein with major human health...
TAR DNA binding protein of 43 kD (TDP-43) is an evolutionarily conserved, ubiquitously expressed transcription factor and RNA-binding protein with major human health relevance. TDP-43 is present in Sertoli and germ cells of the testis and is aberrantly expressed in the sperm of infertile men. Sertoli cells play a key role in spermatogenesis by offering physical and nutritional support to male germ cells. The current study investigated the requirement of TDP-43 in Sertoli cells. Conditional knockout (cKO) of TDP-43 in mouse Sertoli cells caused failure of spermatogenesis and male subfertility. The cKO mice showed decreased testis weight, and low sperm count. Testis showed loss of germ cell layers, presence of vacuoles, and sloughing of round spermatids, suggesting loss of contact with Sertoli cells. Using a biotin tracer, we found that the blood-testis barrier (BTB) was disrupted as early as postnatal day 24 and worsened in adult cKO mice. We noted aberrant expression of the junction proteins connexin-43 (gap junction) and N-cadherin (ectoplasmic specialization). Oil Red O staining showed a decrease in lipid droplets (phagocytic function) in tubule cross-sections, Sertoli cells cytoplasm, and in the lumen of seminiferous tubules of cKO mice. Finally, qRT-PCR showed upregulation of genes involved in the formation and/or maintenance of Sertoli cell junctions as well as in the phagocytic pathway. Sertoli cells require TDP-43 for germ cell attachment, formation and maintenance of BTB, and phagocytic function, thus indicating an essential role for TDP-43 in the maintenance of spermatogenesis.
Topics: Animals; Male; Mice; Blood-Testis Barrier; DNA-Binding Proteins; Semen; Sertoli Cells; Spermatids; Spermatogenesis; Testis
PubMed: 35986894
DOI: 10.1093/biolre/ioac165 -
Experimental and Clinical... Nov 2021Stroke exacts a heavy toll on death and disability worldwide. In animal studies, cell transplant has shown a positive effect by inducing neurogenesis, angiogenesis, and...
OBJECTIVES
Stroke exacts a heavy toll on death and disability worldwide. In animal studies, cell transplant has shown a positive effect by inducing neurogenesis, angiogenesis, and modulating inflammation. Cell transplant therapy could provide researchers with new strategies for treating stroke. The mechanistic target of rapamycin is a central signaling pathway for coordination and control; the administration of rapamycin, a key modulator of this pathway, could be a new therapeutic approach in neurological disorders.
MATERIALS AND METHODS
Adult rats were grouped into 5 main groups: control, sham, rapamycin receiving, Sertoli cell receiving, and rapamycin plus Sertoli cell receiving groups. Sertoli cells were taken from another rat tissue and injected into the right striatum region. After 5 days, ischemic induction was performed, and rapamycin injection (300 mg/kg) was performed 1 hour before surgery. After 24 hours, some regions of the brain, including the cortex, striatum, and piriform cortex-amygdala, were isolated for evaluation.
RESULTS
Our results showed that infarct volume, brain edema, and blood-brain barrier permeability assessments were significantly reduced in some areas of the brain in rats that received rapamycin plus Sertoli cells compared with results shown in the control group.
CONCLUSIONS
Pretreatment with Sertoli cell transplant plus rapamycin injection may enhance neural survival during ischemia through increased glial cell-derived neurotrophic factor and vascular endothelial growth factor, inhibiting the mechanistic target of rapamycin pathway and increasing autophagy performance.
Topics: Animals; Brain Ischemia; Cell Transplantation; Humans; Infarction, Middle Cerebral Artery; Ischemia; Male; Rats; Sertoli Cells; Sirolimus; Stroke; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 34812711
DOI: 10.6002/ect.2021.0198 -
Biology of Reproduction Dec 2021Sertoli cells are a critical component of the testis environment for their role in maintaining seminiferous tubule structure, establishing the blood-testis barrier, and...
Sertoli cells are a critical component of the testis environment for their role in maintaining seminiferous tubule structure, establishing the blood-testis barrier, and nourishing maturing germ cells in a specialized niche. This study sought to uncover how Sertoli cells are regulated in the testis environment via germ cell crosstalk in the mouse. We found two major clusters of Sertoli cells as defined by their transcriptomes in Stages VII-VIII of the seminiferous epithelium and a cluster for all other stages. Additionally, we examined transcriptomes of germ cell-deficient testes and found that these existed in a state independent of either of the germ cell-sufficient clusters. Altogether, we highlight two main transcriptional states of Sertoli cells in an unperturbed testis environment, and a germ cell-deficient environment does not allow normal Sertoli cell transcriptome cycling and results in a state unique from either of those seen in Sertoli cells from a germ cell-sufficient environment.
Topics: Animals; Male; Mice; Sertoli Cells; Signal Transduction; Spermatozoa
PubMed: 34494084
DOI: 10.1093/biolre/ioab160 -
Cell Reports Apr 2020Sertoli cells are supporting cells of the testicular seminiferous tubules, which provide a nurturing environment for spermatogenesis. Adult Sertoli cells are polarized...
Sertoli cells are supporting cells of the testicular seminiferous tubules, which provide a nurturing environment for spermatogenesis. Adult Sertoli cells are polarized so that they can simultaneously support earlier-stage spermatogenic cells (e.g., spermatogonia) basally and later-stage cells (e.g., spermatids) apically. To test the consequences of disrupting cell polarity in Sertoli cells, we perform a Sertoli-specific conditional deletion of Rac1, which encodes a Rho GTPase required for apicobasal cell polarity. Rac1 conditional knockout adults exhibit spermatogenic arrest at the round spermatid stage, with severe disruption of Sertoli cell polarity, and show increased germline and Sertoli cell apoptosis. Thus, Sertoli Rac1 function is critical for the progression of spermatogenesis but, surprisingly, is dispensable for fetal testicular development, adult maintenance of undifferentiated spermatogonia, and meiotic entry. Our data indicate that Sertoli Rac1 function is required only for certain aspects of spermatogenesis and reveal that there are distinct requirements for cell polarity during cellular differentiation.
Topics: Animals; Cell Differentiation; Cell Polarity; Male; Mice; Mice, Inbred C57BL; Neuropeptides; Seminiferous Tubules; Sertoli Cells; Spermatids; Spermatogenesis; Spermatogonia; Testis; rac1 GTP-Binding Protein
PubMed: 32294451
DOI: 10.1016/j.celrep.2020.03.077