Crosstalk between Sertoli and Germ Cells in Male Fertility

doi:10.1016/j.molmed.2019.09.006

Trends in Molecular Medicine

Volume 26, Issue 2, February 2020, Pages 215-231

https://doi.org/10.1016/j.molmed.2019.09.006 Get rights and content

Highlights

The testis produces three endogenous regulatory bioactive peptides known as F5-, NC1-, and LG3/4/5-peptide to modulate blood–testis barrier (BTB) and spermatogenic functions.
F5- and NC1-peptide promote BTB remodeling by making the barrier ‘leaky’ and facilitate the degeneration of adhesion sites at the Sertoli–spermatid interface known as the apical ectoplasmic specialization (ES), to support the transport of preleptotene spermatocytes across the immunological barrier and the release of sperm at spermiation.
LG3/4/5-peptide, however, promotes BTB function by making the barrier ‘tighter’, and promotes spermatid adhesion in the testis.
These three bioactive peptides thus serve as molecular switches that can turn various cellular events ‘on’ or ‘off’ during the epithelial cycle of spermatogenesis.

Spermatogenesis is supported by intricate crosstalk between Sertoli cells and germ cells including spermatogonia, spermatocytes, haploid spermatids, and spermatozoa, which takes place in the epithelium of seminiferous tubules. Sertoli cells, also known as ‘mother’ or ‘nurse’ cells, provide nutrients, paracrine factors, cytokines, and other biomolecules to support germ cell development. Sertoli cells facilitate the generation of several biologically active peptides, which include F5-, noncollagenous 1 (NC1)-, and laminin globular (LG)3/4/5-peptide, to modulate cellular events across the epithelium. Here, we critically evaluate the involvement of these peptides in facilitating crosstalk between Sertoli and germ cells to support spermatogenesis and thus fertility. Modulating or mimicking the activity of F5-, NC1-, and LG3/4/5-peptide could be used to enhance the transport across the blood–testis barrier (BTB) of contraceptive drugs or to treat male infertility.

Section snippets

Biologically Active Biomolecules That Mediate Crosstalk Between Cells in the Seminiferous Epithelium

Through spermatogenesis, millions of sperm are produced on a daily basis. During spermatogenesis, cellular events pertinent to (i) self-renewal of undifferentiated spermatogonia via mitosis, (ii) the production of haploid spermatids via meiosis I/II, (iii) the differentiation of spermatids to spermatozoa via spermiogenesis, and (iv) the release of sperm at spermiation are supported by intricate crosstalk between Sertoli cells and between Sertoli and germ cells [1, 2, 3, 4, 5]. A single

F5-Peptide Modulates Cell Adhesive Function to Support Spermatogenesis

In the mammalian testis, the unique cell–cell AJ designated the ES is expressed at the Sertoli–spermatid (step-8–19 spermatids in rats) interface called the apical ES as well as at the Sertoli cell–cell interface designated the basal ES (Figure 1) [28,29]. The ES is typified by the presence of actin filament bundles that lay in parallel to the plasma membrane in Sertoli cells, sandwiched between the adjacent plasma membranes of the apposing Sertoli cell–elongated spermatid and the cisternae of

Mechanistic Insights into F5-Peptide/p-FAK-Y407 Signaling in BTB Remodeling

FAK was first reported to be a component of the ES in studies using a specific antibody that localized FAK near the basement membrane [37], at the base of the seminiferous epithelium, adjacent to Sertoli cells and undifferentiated spermatogonial cells and is the modified form of ECM in mammalian testes [38]. Subsequent studies have shown that p-FAK-Y397 is robustly expressed at the apical ES from late stage VII through late VIII until the release of sperm at spermiation, supporting the notion

NC1-Peptide: A New Regulatory Protein to Support Apical ES and Basal ES/BTB Function

Besides laminins [42, 43, 44], collagens are another major structural constituent of the basement membrane [45, 46, 47]. One of the major collagen chains in the basement membrane is the collagen α3 (IV) chain [42]. Each monomer of the type IV collagen is assembled from three α3 chains, creating a triple-helical structure [47] (Figure 3). Each chain has an N-terminal noncollagenous 7S domain comprising ∼15 amino acid residues, a long central collagenous domain of ∼1400 residues comprising

LG3/4/5-Peptide Supports Sertoli Cell TJ Barrier Function

The basement membrane in the testis comprises laminins, collagen (type IV) chains, nidogens, and heparan sulfate proteoglycans [38,42,64,65]. Functional laminins are heterotrimers of α-, β-, and γ-chains. To date, there are five α-, three β-, and three γ-chains, giving rise to at least 15 protein isoforms via different combinations that are found in different tissues [65,66] (Figure 4). The laminin-α1 and -α5 chains are involved in early embryonic development and/or organogenesis, while

The mTORC1/rpS6/Akt1/2 Signaling Complex in LG3/4/5-Peptide-Mediated Effects on Sertoli Cell TJ Barrier Function

Laminin-α2 knockdown in Sertoli cells by RNAi was found to display considerable upregulation of the expression of p-rpS6-S235/S236 and p-rpS6-S240/S244, with concomitant downregulation of p-Akt1-S473 and p-Akt2-S474 [20], implicating mTORC1/rpS6/Akt1/2 as the downstream signaling pathway utilized by LG3/4/5-peptide to modulate spermatogenic function, such as the BTB function (Figure 2). Earlier studies have shown that the mTORC1/rpS6 signaling complex modulates Sertoli cell BTB function through

Role of F5-, NC1-, and LG3/4/5-Peptides in Mediating Crosstalk to Support Spermatogenesis: A Hypothesis

As shown in Figure 1, we propose a model wherein the testis utilizes F5-, NC1-, and LG3/4/5-peptides to modulate spermatogenic functions through their differential effects on the BTB and spermatid adhesion across the seminiferous epithelium. For instance, the F5-peptide generated from the laminin-γ3 chain at the apical ES promotes BTB remodeling, such as of the ‘old’ BTB located above the preleptotene spermatocytes to support their transport across the barrier, but also potentiates degeneration

Clinical Potential

Recent studies in adult Sprague–Dawley rats have shown that F5-, NC1-, and LG3/4/5-peptides, and some of their downstream signaling proteins such as the mTORC1/rpS6 signaling complex and p-FAK-Tyr407 (Figure 2), could possibly be used to modify blood–tissue barrier function. The action of these peptides and/or biomolecules can in turn modify drug transport function at the BTB. In brief, if the permeability of the BTB can be transiently modified by one of these peptides, such as F5-peptide [18,19

Concluding Remarks

We have provided a hypothetical model by which these three bioactive peptides mediate crosstalk between Sertoli and germ cells to modulate junction remodeling to support spermatogenesis as noted in Figure 1. However, since these peptides exert their effects through changes in the cytoskeletal organization of F-actin and MTs across the seminiferous epithelium, it is likely that these bioactive peptides also modulate other cellular events pertinent to spermatogenesis, such as meiosis I and II,

Acknowledgments

This work was supported in part by grants from the National Institutes of Health (NICHD, R01 HD056034 to C.Y.C.), National Natural Science Foundation of China (81730042 to R.G.), and Science and Technology Department of Zhejiang Province (2019C03035 to R.G.).

Glossary

Adherens junction (AJ): actin-based cell–cell anchoring junction in epithelia or endothelia, usually located behind an actin-based TJ. An AJ is usually created by adhesion protein complexes such as cadherin/catenin and nectin/afadin linked to the actin cytoskeleton.
Blood–testis barrier (BTB): one of the tightest blood–tissue barriers that provides a transcellular and paracellular barrier by restricting the diffusion of water, electrolytes, macromolecules, and biomolecules across the Sertoli cell

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Decabromodiphenyl ether (BDE-209), a frequently used brominated flame retardant, readily enters the environment and is difficult to degrade with bioaccumulation. BDE-209 could cause male reproductive toxicity, but the regulatory functions of Sertoli cells-secreted factors remain uncertain. In present study, male mice were treated with 75 mg/kg BDE-209 and then stopped exposure for 50 days. Exogenous Glial cell line-derived neurotrophic factor (GDNF), a Sertoli cell-secreted factor, was injected into testes of mice treated with BDE-209 for 50 days to explore the role of GDNF in BDE-209-induced reproductive toxicity. The mouse spermatogonia cell line GC-1 spg was used in vitro to further verify regulatory effects of Sertoli cells-secreted factors on meiotic initiation. The results showed that BDE-209 inhibited expressions of the self-renewal pathway GFRα-1/RAS/ERK1/2 in spermatogonial stem cells (SSCs), and reduced expressions of spermatogonia proliferation-related pathway NRG3/ERBB4 and meiosis initiation factor Stra8. Furthermore, BDE-209 decreased the levels of both GDNF and retinoic acid (RA) secreted by Sertoli cells in testes. Importantly, the alterations of above indicators induced by BDE-209 did not recover after 50-day recovery period. After exogenous GDNF injection, the decreased expression of GFRα-1/RAS/ERK in SSCs was reversed. However, the level of RA and expressions of NRG3/ERBB4/Stra8 were not restored. The in vitro experimental results showed that exogenous RA reversed the reductions in NRG3/ERBB4/Stra8 and ameliorated inhibition of GC-1 spg cells proliferation induced by BDE-209. These results suggested that Sertoli cells-secreted factors play roles in regulating various stages of germ cell development. Specifically, BDE-209 affected the self-renewal of SSCs by decreasing GDNF secretion resulting in the inhibition of GFRα-1/RAS/ERK pathway; BDE-209 hindered the proliferation of spermatogonia and initiation of meiosis by inhibiting the secretion of RA and preventing RA from binding to RARα, resulting in the suppression of NRG3/ERBB4/Stra8 pathway. As a consequence, spermatogenesis was compromised, leading to persistent male reproductive toxicity.
Restoration of fertility in nonablated recipient mice after spermatogonial stem cell transplantation
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Spermatogonial stem cell (SSC) transplantation is a valuable tool for studying stem cell-niche interaction. However, the conventional approach requires the removal of endogenous SSCs, causing damage to the niche. Here we introduce WIN18,446, an ALDH1A2 inhibitor, to enhance SSC colonization in nonablated recipients. Pre-transplantation treatment with WIN18,446 induced abnormal claudin protein expression, which comprises the blood-testis barrier and impedes SSC colonization. Consequently, WIN18,446 increased colonization efficiency by 4.6-fold compared with untreated host. WIN18,446-treated testes remained small despite the cessation of WIN18,446, suggesting its irreversible effect. Offspring were born by microinsemination using donor-derived sperm. While WIN18,446 was lethal to busulfan-treated mice, cyclophosphamide- or radiation-treated animals survived after WIN18,446 treatment. Although WIN18,446 is not applicable to humans due to toxicity, similar ALDH1A2 inhibitors may be useful for SSC transplantation into nonablated testes, shedding light on the role of retinoid metabolism on SSC-niche interactions and advancing SSC research in animal models and humans.
Cross-talk between Vimentin and autophagy regulates blood-testis barrier disruption induced by cadmium
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The blood-testis barrier (BTB) plays a vital role in mammalian spermatogenesis by separating the seminiferous epithelium into an adluminal and a basal compartment. Cadmium (Cd) is a toxic heavy metal that is widely present in the environment. We observed that Cd can induce BTB disruption, leading to apoptosis of testicular cells. However, the molecular mechanisms contributing to BTB injury induced by Cd have not yet been fully clarified. Vimentin (Vim) is an important desmosome-like junction protein that mediates robust adhesion in the BTB. In this study, we investigated how Vim responds to Cd. We found that Cd treatment led to a significant decrease in Vim expression, accompanied by a marked increase in LC3-II expression and a higer number of autophagosomes. Interestingly, we also observed that Cd-induced autophagy was associated with decreased Vim activity and enhanced apoptosis of testicular cells. To further investigate the role of autophagy in Vim regulation under Cd exposure, we treated cells with an autophagy inhibitor called 3-MA. We found that 3-MA treatment enhanced Vim expression and improved the disruption of the BTB under Cd exposure. Additionally, the inhibition of Vim confirmed the role of autophagy in modulating Vim expression. These results reveal a previously unknown regulatory mechanism of Cd involving the interplay between a heavy metal and a protein.
Cadmium exposure induces pyroptosis of TM4 cells through oxidative stress damage and inflammasome activation
2024, Ecotoxicology and Environmental Safety
Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11–7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.
Fluorochloridone induces mitochondrial dysfunction and apoptosis in primary goat Sertoli cells
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Fluorochloridone (FLC), a pyrrolidone herbicide, has been recognized as a hazardous chemical. The in vitro adverse effects of FLC on the reproduction of livestock have not been assessed. This study was conducted to explore the cytotoxicity and toxicological mechanisms of FLC on cultured goat Sertoli cells. The results showed that FLC exposure significantly decreased goat Sertoli cell viability (p < 0.05) and induced oxidative stress. And FLC treatment promoted apoptosis and initiation of autophagy. Interestingly, FLC inhibited lysosomal biogenesis and blocked autophagic flux in goat Sertoli cells. The expression levels of autophagy-related proteins Atg5, LC3II, and p62 were significantly increased (p < 0.05) in FLC-treated goat Sertoli cells compared with the control. Importantly, FLC-induced ROS accumulation further causes mitochondrial dysfunction and disturbs mitophagy. FLC significantly decreased (p < 0.05) the expression levels of OPA1, MFN2, p-Drp1, FIS1, PINK1, and Parkin in goat Sertoli cells. Moreover, pretreatment with N-acetyl-l-cysteine (NAC, an antioxidant) significantly reduced (p < 0.01) FLC-induced ROS accumulation and reversed the disorder of autophagy levels. Our results indicated that FLC-induced toxicity in primary goat Sertoli cells was characterized by ROS accumulation, inducing oxidative stress, inhibiting lysosomal biogenesis, blocking autophagic flux, and promoting mitochondrial dysfunction, resulting in apoptosis via the mitochondrial pathway.
Wuzi Yanzong administration alleviates Sertoli cell injury by recovering AKT/mTOR-mediated autophagy and the mTORC1–mTROC2 balance in aging-induced testicular dysfunction
2024, Journal of Ethnopharmacology
Wuzi Yanzong Prescription (WZ), a classic traditional Chinese medicine formula, has the properties of kidney nourishing and essence strengthening, and it is widely used to treat male infertility with a long history. Sertoli cells are injured with aging, resulting in testicular dysfunction, and WZ effectively rejuvenates the age-related decline of testicular function. However, whether the therapeutic effects of WZ on aging-related testicular dysfunction are dependent on the restoration of Sertoli cell function remains unclear.
In a mouse model of natural aging, we explored the protective effects of WZ and its potential mechanisms.
Fifteen-month-old C57BL/6 mice were randomized to receive either standard diet or WZ (2 and 8 g/kg) for 3 months. Meanwhile, 10 1-month-old mice were considered the adult control group and received standard diet for 3 months. The testis and epididymis were rapidly collected, and the sperm quality, testicular histology, Sertoli cell numbers, tight junction (TJ) ultrastructure, and blood–testis barrier-associated protein expression and localization were assessed.
WZ significantly increased sperm concentration and sperm viability, improved the degenerative histomorphology and elevated the seminiferous epithelium height. Furthermore, WZ increased the number of Sertoli cells, restored the ultrastructure of the Sertoli cell TJ, and upregulated the expression of TJ-associated proteins (zonula occludens-1 and Claudin11), ectoplasm specialized-associated proteins (N-Cadherin, E-Cadherin and β-Catenin), and gap junction-associated protein (connexin 43), but did not affect the expression of Occludin and cytoskeletal protein (Vimentin). In addition, WZ did not change the localization of zonula occludens-1 and β-Catenin in aged testis. Moreover, WZ increased the expression of autophagy-associated proteins (light chain 3 beta and autophagy related 5) and decreased the expression of p62, phosphorylated mammalian target of rapamycin, and phosphorylated AKT in Sertoli cells. Finally, we found that WZ attenuated mTOR complex 1 (mTORC1) activity and upregulated mTORC2 activity, as evidenced by inhibition of the expression of the regulatory-associated protein of mTOR, phosphorylated p70 S6K, and phosphorylated ribosomal protein s6 and enhancement of the expression of Rictor in the Sertoli cells of aging mice.
WZ improves the injury of Sertoli cells by restoring AKT/mTOR-mediated autophagy and the mTORC1–mTROC2 balance in Sertoli cells during aging. Our findings provide a new mechanism of WZ in the treatment of aging-induced testicular dysfunction.

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⁴: These authors contributed equally

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Trends in Molecular Medicine

ReviewCrosstalk between Sertoli and Germ Cells in Male Fertility

Highlights

Section snippets

Biologically Active Biomolecules That Mediate Crosstalk Between Cells in the Seminiferous Epithelium

F5-Peptide Modulates Cell Adhesive Function to Support Spermatogenesis

Mechanistic Insights into F5-Peptide/p-FAK-Y407 Signaling in BTB Remodeling

NC1-Peptide: A New Regulatory Protein to Support Apical ES and Basal ES/BTB Function

LG3/4/5-Peptide Supports Sertoli Cell TJ Barrier Function

The mTORC1/rpS6/Akt1/2 Signaling Complex in LG3/4/5-Peptide-Mediated Effects on Sertoli Cell TJ Barrier Function

Role of F5-, NC1-, and LG3/4/5-Peptides in Mediating Crosstalk to Support Spermatogenesis: A Hypothesis

Clinical Potential

Concluding Remarks

Acknowledgments

Glossary

Semin. Cell Dev. Biol.

Biochem. Biophys. Acta

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

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Gene

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Biochem. Pharmacol.

J. Neuroimmunol.

Neuromuscul. Disord.

FEBS Lett.

Cell junction dynamics in the testis: Sertoli–germ cell interactions and male contraceptive development

Physiol. Rev.

Sertoli–Sertoli and Sertoli–germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis

Endocr. Rev.

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 1: background to spermatogenesis, spermatogonia, and spermatocytes

Microsc. Res. Tech.

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 2: changes in spermatid organelles associated with development of spermatozoa

Microsc. Res. Tech.

The cytology of the testis

Novel stage classification of human spermatogenesis based on acrosome development

Biol. Reprod.

Spermatogenesis and cycle of the seminiferous epithelium

Adv. Exp. Med. Biol.

Germ cell transport across the seminiferous epithelium during spermatogenesis

Physiology

A revised model for spermatogonial expansion in man: lessons from non-human primates

Reproduction

Spermatogonial stem cells: questions, models and perspectives

Hum. Reprod. Update

Sertoli–Sertoli and Sertoli–germ cell communications

Microsc. Res. Tech.

Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage-gated channels, methylation/acetylation, and transcription factors

Microsc. Res. Tech.

Physiological and physiopathological aspects of connexins and communicating gap junctions in spermatogenesis

Philos. Trans. R. Soc. Lond. B Biol. Sci.

Cross-talk between tight and anchoring junctions – lesson from the testis

Adv. Exp. Med. Biol.

A local autocrine axis in the testes that regulates spermatogenesis

Nat. Rev. Endocrinol.

A peptide derived from laminin-γ3 reversibly impairs spermatogenesis in rats

Nat. Commun.

F5-peptide induces aspermatogenesis by disrupting organization of actin- and microtubule-based cytoskeletons in the testis

Oncotarget

Basement membrane laminin α2 regulation of BTB dynamics via its effects on F-actin and microtubule (MT) cytoskeletons is mediated through mTORC1 signaling

Endocrinology

Regulation of the blood–testis barrier by a local axis in the testis: role of laminin α2 in the basement membrane

FASEB J

Focal adhesion kinase-Tyr407 and -Tyr397 exhibit antagonistic effects on blood–testis barrier dynamics in the rat

Proc. Natl Acad. Sci. U. S. A.

Perfluorooctanesulfonate (PFOS) perturbs male rat Sertoli cell blood–testis barrier function by affecting F-actin organization via p-FAK-Tyr407 – an in vitro study

Endocrinology

Review
Crosstalk between Sertoli and Germ Cells in Male Fertility

Focal adhesion kinase-Tyr⁴⁰⁷ and -Tyr³⁹⁷ exhibit antagonistic effects on blood–testis barrier dynamics in the rat

Perfluorooctanesulfonate (PFOS) perturbs male rat Sertoli cell blood–testis barrier function by affecting F-actin organization via p-FAK-Tyr⁴⁰⁷ – an in vitro study