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Sertoli cell

Sertoli cells are tall, columnar somatic cells located in the seminiferous tubules of the testes, serving as essential nurse cells that support spermatogenesis by providing nutrients, structural scaffolding, and forming the blood-testis barrier to protect developing germ cells from immune attack.^[1] Discovered by Italian physiologist Enrico Sertoli in 1865 through microscopic examination of human testicular tissue, these cells are named after him and are identifiable by their large size, pale and irregular nuclei, and extensive cytoplasmic branches that envelop and nurture germ cells from spermatogonia to spermatozoa.^[1]^[2] Their absence or dysfunction can lead to infertility, as seen in conditions like Sertoli cell-only syndrome, underscoring their indispensable role in male reproduction.^[1] Morphologically, Sertoli cells extend from the basal lamina of the seminiferous epithelium to the lumen, forming tight junctions with neighboring Sertoli cells to create the blood-testis barrier, a selective permeability structure that compartmentalizes the seminiferous epithelium into basal and adluminal compartments.^[2]^[3] This barrier, established during puberty under androgen influence, prevents autoimmune responses against post-meiotic germ cells by isolating them from systemic circulation while allowing nutrient transport.^[3] The cells exhibit remarkable plasticity, adapting their shape and function across vertebrate species—from proliferative roles in fish and amphibians to a post-pubertal static state in mammals—and respond dynamically to hormonal signals throughout the spermatogenic cycle.^[2] Functionally, Sertoli cells orchestrate spermatogenesis through paracrine and endocrine signaling, secreting key factors such as androgen-binding protein (ABP) to concentrate testosterone locally, inhibin B to regulate follicle-stimulating hormone (FSH) feedback, and glial cell line-derived neurotrophic factor (GDNF) to maintain the spermatogonial stem cell niche.^[1]^[3] They act as phagocytes, clearing residual bodies and apoptotic germ cells, and provide metabolic support via nutrients like lactate, transferrin for iron delivery, and retinoic acid to trigger germ cell differentiation and meiosis.^[3] Regulated primarily by FSH from the pituitary and testosterone from Leydig cells, Sertoli cells also contribute to testicular immune privilege and embryonic sex determination by producing anti-Müllerian hormone (AMH) under SRY and SOX9 gene control.^[1]^[2] In clinical contexts, testicular Sertoli cell tumors can cause hormone imbalances, such as gynecomastia due to estrogen production, while their therapeutic potential is explored in transplantation for restoring fertility.^[1]^[4]

Anatomy and Structure

Location and Morphology

Sertoli cells are tall, columnar epithelial cells located within the seminiferous tubules of the testes, where they line the tubular walls and extend from the basement membrane to the apical lumen.^[1] These cells form the structural basis of the seminiferous epithelium, attaching to the basal lamina in the basolateral portion of the tubules and spanning the full height of the epithelium.^[1] They were first described in 1865 by Enrico Sertoli as branched, supportive elements in human testicular tissue.^[2] Morphologically, Sertoli cells exhibit an irregular, pyramidal, or elongated shape, characterized by a large, pale, oval nucleus positioned basally with a prominent nucleolus and often deep indentations.^[1] Their extensive cytoplasm forms thin, branching arms less than 50 nm wide, which can cover a surface area of up to 16,000 μm², creating a dynamic, irregular outline that adapts to the surrounding germ cells.^[2] Tight junctions between adjacent Sertoli cells establish a compartmental barrier within the epithelium.^[1] During the spermatogenic cycle, Sertoli cell shape and size vary cyclically; they elongate and become more irregular in active phases to accommodate germ cell development, with nuclei occasionally shifting apically toward the lumen during spermiation in rodents.^[2] Each Sertoli cell can envelop and support up to 40 developing germ cells at various stages, holding primitive spermatogonia near the basement membrane and mature spermatids near the apex via cup-like cytoplasmic crypts.^[1] Additionally, these cells exhibit phagocytic activity, engulfing residual bodies—excess cytoplasm shed by spermatids during maturation.^[2]

Cellular Ultrastructure

Sertoli cells exhibit a highly specialized ultrastructure adapted to their supportive role in the seminiferous epithelium, characterized by prominent organelles and cytoskeletal networks visible under electron microscopy. The cytoplasm contains an extensive array of membranous and filamentous components that facilitate intracellular processes essential for germ cell nurturing.^[2] The endoplasmic reticulum in Sertoli cells is notably abundant, with smooth endoplasmic reticulum (SER) forming extensive cisternae involved in lipid metabolism and associated with ectoplasmic specializations and tubulobulbar complexes.^[2] This SER network supports steroidogenic activities by providing a platform for cholesterol processing and hormone precursor synthesis.^[5] In contrast, rough endoplasmic reticulum (RER) is present throughout the cytoplasm, featuring ribosomes that enable robust protein synthesis for cellular maintenance and secretion.^[2] The Golgi apparatus, well-developed and positioned near the nucleus, consists of stacked cisternae that process and package proteins into secretory vesicles, ensuring efficient trafficking within the cell.^[2] ^[6] Cytoskeletal elements form a dynamic scaffold in Sertoli cells, maintaining structural integrity and enabling intracellular transport. Actin filaments are particularly abundant in ectoplasmic specializations, forming dense bundles that anchor germ cells and contribute to the blood-testis barrier's tightness via junctional complexes.^[2] Microtubules organize into parallel tracts linked to the endoplasmic reticulum, facilitating the directional transport of spermatids and organelles along the cell's elongated processes.^[2] Intermediate filaments, primarily vimentin, encircle nuclear membrane indentations and provide mechanical support against cytoskeletal stresses during spermatogenesis.^[2] Lysosomes and phagosomes are numerous in the Sertoli cell cytoplasm, appearing as membrane-bound vesicles that engulf and degrade apoptotic germ cells and residual bodies released during spermiation.^[2] These organelles contain hydrolytic enzymes that break down cellular debris, recycling components such as iron, which is delivered to germ cells via Sertoli cell-produced transferrin for use in cellular processes including DNA synthesis and enzymatic functions.^[3] Mitochondria are distributed variably throughout the Sertoli cell cytoplasm, with higher concentrations in the basal region near the basement membrane to support energy-intensive metabolic demands.^[2] These organelles, featuring cristae-rich matrices, generate ATP via oxidative phosphorylation tailored to the cell's glycolytic and lipolytic preferences, ensuring sustained energy provision for phagocytic and transport functions.^[5]

Development and Origin

Embryonic Development

Sertoli cells originate from the coelomic epithelium of the mesodermal layer in the developing gonad, specifically within the genital ridge.^[7] In genetic males (XY embryos), the SRY gene on the Y chromosome initiates testis determination by directing the differentiation of these precursor cells into Sertoli cells, typically around the 6th to 7th week of human gestation.^[8] This process begins with the expression of SRY in pre-Sertoli cells, which migrate from the coelomic epithelium into the underlying mesenchyme of the genital ridge.^[9] Key signaling pathways drive the specification of Sertoli cells following SRY activation. The SRY protein upregulates SOX9, a transcription factor essential for committing precursor cells to the Sertoli lineage and maintaining male gonadal development.^[10] Additionally, fibroblast growth factor 9 (FGF9), secreted by early Sertoli precursors, reinforces SOX9 expression through a positive feedback loop, promoting Sertoli cell differentiation and suppressing ovarian pathways.^[11] These molecular interactions ensure the stabilization of the male fate during this critical window. Following specification, pre-Sertoli cells undergo rapid proliferation within the genital ridge, expanding the population necessary for testicular morphogenesis.^[12] By approximately 7 to 8 weeks of gestation in humans, differentiating Sertoli cells aggregate around primordial germ cells to form testis cords, which represent the foundational architecture of the seminiferous tubules.^[13] This cord formation establishes the basic compartmentalization of the testis, separating germ cells from interstitial components and setting the stage for further organogenesis.^[9]

Postnatal Maturation

During the postnatal period, Sertoli cells in the human testis remain largely quiescent following an initial wave of proliferation in infancy, with limited mitotic activity observed from approximately 1 to 10 years of age.^[14] This dormancy ensures a stable cellular population during childhood, preparing the testis for the demands of puberty without excessive growth.^[15] At the onset of puberty, around ages 10-14 in humans, Sertoli cells undergo a profound phase of proliferation and differentiation, primarily driven by follicle-stimulating hormone (FSH) and testosterone. FSH, acting through cAMP/PKA and PI3K/Akt/mTORC1 signaling pathways, stimulates cell division and initiates maturation by upregulating genes such as Klf4 and structural proteins like N-cadherin and claudin-11.^[16] Testosterone complements these effects by binding to androgen receptors, enhancing FSH receptor expression, promoting cell elongation, and increasing cytoplasmic volume to support expanded functional roles.^[14] These hormonal cues consolidate the blood-testis barrier (BTB), forming tight junctions that isolate adluminal germ cells and prevent immune surveillance, a critical step completed by mid-puberty.^[15] This pubertal transition enables Sertoli cells to acquire full secretory capacity, including the production of nutrients like lactate for germ cell metabolism, and nurturing abilities to guide spermatogonial differentiation into spermatozoa.^[16] In adulthood, Sertoli cells enter a state of lifelong maintenance with negligible mitotic activity, resulting in a fixed number per testis that dictates the organ's sperm output potential.^[17] FSH continues to sustain these mature functions via cAMP-mediated pathways, ensuring ongoing support for spermatogenesis without further population expansion.^[16]

Primary Functions

Spermatogenesis Support

Sertoli cells play a central role in supporting spermatogenesis by providing essential nutrients and growth factors to developing germ cells, including spermatogonia, spermatocytes, and spermatids. These somatic cells supply metabolic substrates such as lactate, which serves as a primary energy source for germ cells, and iron transported via transferrin to support cellular proliferation and differentiation. Additionally, Sertoli cells secrete growth factors like glial cell line-derived neurotrophic factor (GDNF) to maintain spermatogonial stem cell self-renewal and promote their differentiation, as well as retinoic acid (RA) to drive meiotic initiation in spermatogonia.^[3] These provisions create a nutrient-rich microenvironment that sustains germ cell viability and progression through the spermatogenic stages.^[3] Physical attachment between Sertoli cells and germ cells is mediated by specialized junctions that anchor and guide germ cell development. Adherens junctions, composed of cadherins and catenins, form stable attachments primarily with spermatogonia and preleptotene spermatocytes, facilitating their migration along the basal lamina. Ectoplasmic specializations, unique actin-based structures at the Sertoli-germ cell interface, provide robust anchorage for elongating spermatids, preventing premature release and enabling proper acrosome and flagellum formation during spermiogenesis. These junctions not only offer mechanical support but also enable bidirectional signaling that coordinates germ cell positioning and maturation.^[3]^[18] Sertoli cells maintain seminiferous tubular hygiene through active phagocytosis of residual bodies shed by maturing spermatids and apoptotic germ cells, preventing accumulation of cellular debris that could impair spermatogenesis. During spermiogenesis, spermatids release cytoplasmic residual bodies containing excess organelles, which are rapidly engulfed by Sertoli cells via receptor-mediated endocytosis, often involving scavenger receptors like SR-B1. Similarly, apoptotic spermatogonia and spermatocytes are cleared to avoid inflammatory responses and recycle nutrients, such as iron from engulfed cells. This phagocytic activity is stage-specific, peaking in late stages of the seminiferous epithelial cycle, and ensures efficient waste removal while supporting Sertoli cell metabolism.^[19]^[18] Germ cell entry into meiosis is tightly regulated by Sertoli cells through stage-specific interactions that synchronize developmental timing. In stages VII-IX of the seminiferous cycle, Sertoli cells release pulses of RA that induce preleptotene spermatocytes to express Stra8 and other meiotic genes, committing them to meiotic division while inhibiting spermatogonial proliferation. These interactions involve direct contact via junctional complexes and soluble cues, ensuring only a subset of germ cells progresses to meiosis per cycle, thus maintaining the balance of germ cell populations. Disruptions in these stage-specific signals lead to meiotic arrest or overproliferation.^[3]^[20] The progression of the spermatogenic wave is coordinated by Sertoli cells via cyclic structural changes in the seminiferous epithelium, ensuring continuous and orderly germ cell development. During the epithelial cycle, Sertoli cell junctions undergo disassembly and reassembly, particularly in stages VII-VIII, where adherens and tight junctions remodel to allow spermatocyte translocation across the blood-testis barrier. These dynamics are regulated by signaling pathways such as TGF-β/Smad, which downregulates junctional proteins like claudin-11, and MAPK, which modulates actin cytoskeleton reorganization. Such cyclic alterations synchronize germ cell cohorts, preventing asynchrony and supporting wave propagation along the tubule.^[21]^[22]

Secretory Activities

Sertoli cells produce several key hormones and proteins essential for regulating spermatogenesis and supporting germ cell development. Inhibin B, secreted primarily by Sertoli cells, acts as a negative feedback regulator of follicle-stimulating hormone (FSH) secretion from the pituitary gland, thereby modulating Sertoli cell activity and overall testicular function.^[3] Androgen-binding protein (ABP), also synthesized by these cells under FSH stimulation, binds testosterone with high affinity to maintain elevated local concentrations within the seminiferous tubules, facilitating androgen-dependent processes in spermatogenesis.^[3] Additionally, transferrin is secreted by Sertoli cells to transport iron to developing germ cells, which is crucial for DNA synthesis during meiosis and preventing oxidative stress in spermatids.^[3] Sertoli cells secrete seminiferous tubule fluid (STF), a specialized luminal fluid that constitutes the majority of the total testicular fluid volume and provides a nutrient-rich environment for germ cells. This fluid is produced at a rate of approximately 10–20 μl per gram of testis per hour and is rich in electrolytes such as potassium (higher than in serum) and nutrients like lactate and inositol, while notably lacking glucose to support germ cell metabolism via alternative pathways.^[23] Testosterone from adjacent Leydig cells enhances STF production, underscoring the hormonal coordination of Sertoli cell secretory functions.^[3] Secretory activities of Sertoli cells exhibit stage-specific patterns synchronized with the cycle of the seminiferous epithelium, ensuring timed delivery of factors during spermatogenesis. For instance, inhibin B levels peak during stages XI–I and are lower in stages IV–VII, correlating with spermatocyte development, while transferrin expression reaches maxima in stages VIII–XIV to coincide with iron demands in later germ cell stages.^[24] These dynamic secretions contribute to fluid resorption and ionic balance within the tubules by regulating paracellular transport across the blood-testis barrier, maintaining low sodium and appropriate ion gradients to prevent osmotic imbalances and support sperm maturation.^[25]

Structural Support

Sertoli cells play a crucial role in maintaining testicular architecture by forming the blood-testis barrier (BTB) through specialized tight junctions between adjacent cells. These tight junctions, primarily composed of integral membrane proteins such as claudin-11 and occludin, seal the intercellular spaces near the basement membrane of the seminiferous tubules, thereby dividing the epithelium into basal and adluminal compartments.^[26]^[27] The basal compartment contains spermatogonia and preleptotene spermatocytes, while the adluminal compartment houses more advanced germ cells, including spermatocytes and spermatids, which express autoantigenic proteins.^[26] This compartmentalization physically restricts the passage of immune cells, antibodies, and other molecules from the bloodstream, thereby protecting post-meiotic germ cells from autoimmune attack and ensuring immune privilege within the testis.^[26]^[27] In addition to barrier formation, Sertoli cells extend elaborate cytoplasmic processes that create a dynamic structural scaffold enveloping developing germ cells throughout the seminiferous epithelium. These branching extensions, rich in cytoskeletal elements like actin filaments and microtubules, physically support and position germ cells at specific stages of spermatogenesis, facilitating their orderly migration from the basal to the adluminal compartment.^[28]^[3] By forming cup-like invaginations around round spermatids and deep clefts for elongated spermatids, these processes provide mechanical stability and guide germ cell translocation across the BTB during junction remodeling.^[28] Sertoli cells also interact closely with the basal lamina, a specialized extracellular matrix layer underlying the seminiferous tubules, to anchor the epithelium and coordinate structural dynamics. These interactions, mediated through integrins and laminins, enable Sertoli cells to maintain tubule integrity while collaborating with surrounding peritubular myoid cells, which are contractile myofibroblast-like cells.^[29] Peritubular myoid cells generate peristaltic contractions that propel spermatozoa and fluid through the tubules, with Sertoli cells contributing to this coordination via basal attachments and signaling cues that synchronize epithelial and peritubular responses.^[30]^[29] The permeability of the BTB is dynamically regulated by hormonal signals, particularly androgens acting through the androgen receptor in Sertoli cells. Androgen receptor activation transcriptionally upregulates tight junction proteins like claudin-3, which transiently reinforces the barrier during spermatogenesis, preventing excessive leakage while allowing controlled germ cell transit.^[31] In androgen-deficient models, such as Sertoli cell-specific androgen receptor knockouts, BTB permeability increases, as evidenced by enhanced penetration of tracers like biotin into the adluminal compartment, highlighting the hormone's essential role in modulating barrier function.^[31]

Immunoregulatory Roles

Immunosuppressive Mechanisms

Sertoli cells actively contribute to the immune-privileged status of the testis by employing multiple immunosuppressive mechanisms that prevent immune-mediated damage to developing germ cells. These processes involve the targeted elimination of activated immune cells, inhibition of inflammatory signaling, and modulation of nutrient availability, collectively fostering a tolerogenic environment. This active suppression complements the physical isolation provided by the blood-testis barrier, ensuring the protection of autoantigenic haploid germ cells from systemic immune surveillance.^[32] One primary mechanism is the Fas-Fas ligand (FasL) interaction, where Sertoli cells constitutively express FasL on their surface. This transmembrane protein binds to Fas receptors on infiltrating T cells, triggering caspase activation and subsequent apoptosis of these immune cells. Studies using testis grafts from mice deficient in functional FasL (gld strain) demonstrated rapid rejection due to unchecked T-cell infiltration, whereas wild-type grafts survived indefinitely, highlighting FasL's role in eliminating activated lymphocytes and maintaining tolerance.^[33]^[34] Sertoli cells also produce transforming growth factor-β (TGF-β), a multifunctional cytokine that suppresses pro-inflammatory responses. TGF-β inhibits the production of cytokines such as interleukin-1 (IL-1) and IL-6 from immune cells, thereby dampening inflammation within the testicular microenvironment. Additionally, TGF-β promotes the differentiation and expansion of regulatory T cells (Tregs), which express Foxp3 and actively suppress autoreactive T-cell responses; co-culture experiments with Sertoli cells and T cells showed sustained Treg generation dependent on TGF-β secretion.^[32] Another key pathway involves indoleamine 2,3-dioxygenase (IDO), an enzyme expressed by Sertoli cells that catalyzes the degradation of tryptophan into kynurenine. This depletes local tryptophan levels, an essential amino acid required for T-cell proliferation, effectively starving and arresting activated T cells in the G1 phase of the cell cycle, rendering them susceptible to apoptosis. In models of experimental autoimmune orchitis, IDO inhibition exacerbated inflammation and germ cell loss, confirming its protective role in sustaining immune privilege.^[35]^[36] Through these coordinated mechanisms—FasL-mediated apoptosis, TGF-β-driven anti-inflammatory signaling, and IDO-induced metabolic suppression—Sertoli cells establish a robust immunosuppressive niche that safeguards haploid germ cells from autoimmunity, preventing conditions like autoimmune orchitis.^[32]^[37] However, Sertoli cells exhibit a dual role in immune regulation, acting as a "double-edged sword" by also contributing to pro-inflammatory responses when necessary. They express Toll-like receptors (TLRs), such as TLR2, TLR3, and TLR4, which detect pathogens and trigger the secretion of pro-inflammatory cytokines including IL-1β, IL-6, and tumor necrosis factor-α (TNF-α). This enables antimicrobial defense but can disrupt the blood-testis barrier if dysregulated, highlighting the balance required for testicular immune homeostasis.^[38]

Key Immunomodulatory Molecules

Sertoli cells secrete activin A, a member of the TGF-β superfamily, which exerts anti-inflammatory effects by promoting the polarization of macrophages toward an M2 phenotype and enhancing the production of regulatory T cells through IL-10 induction.^[38]^[39] This molecule helps maintain immune tolerance in the testis by suppressing pro-inflammatory cytokine release from innate immune cells.^[39] Follistatin, produced by Sertoli cells, acts as a binding protein that neutralizes activin A activity, thereby fine-tuning its immunomodulatory effects to prevent excessive suppression of immune responses during inflammation.^[40] Clusterin, another secreted factor from Sertoli cells, functions as a complement regulatory protein with anti-apoptotic and anti-inflammatory properties; it inhibits the assembly of the membrane attack complex (MAC), protecting germ cells and Sertoli cells from complement-mediated lysis while reducing local inflammation.^[41] Sertoli cells express CD40, a member of the TNF receptor superfamily, which interacts with dendritic cells to maintain low basal CD40 levels and prevent their activation into an inflammatory state following lipopolysaccharide exposure, thereby supporting tolerogenic immune environments.^[38] Additionally, Sertoli cells constitutively express CD95 ligand (CD95L, also known as FasL), which induces apoptosis in Fas-expressing infiltrating T cells, effectively eliminating autoreactive or activated lymphocytes that threaten testicular immune privilege. This mechanism contributes to the suppression of adaptive immune responses against germ cell antigens. Members of the serpin family, such as SERPINA3N (also referred to as SPI-2 in some contexts) and SERPINB9, are expressed and secreted by Sertoli cells to inhibit granzyme B activity from cytotoxic CD8+ T cells and natural killer cells, thereby blocking protease-dependent apoptosis and controlling excessive immune-mediated damage during inflammatory episodes. These inhibitors form stable complexes with granzyme B, preserving Sertoli cell integrity and germ cell survival while modulating the intensity of innate and adaptive immune responses in the testis.^[42] The transcription factor SOX9 plays a central role in regulating the expression of immune-related genes in Sertoli cells by repressing pro-inflammatory pathways; in SOX9-deficient models, Sertoli cells exhibit upregulated expression of inflammation-associated genes, leading to disrupted immune homeostasis and increased susceptibility to autoimmune responses in the testis.^[43] This SOX9-mediated transcriptional control ensures the maintenance of an immunosuppressive milieu essential for spermatogenesis.

Clinical and Pathological Aspects

Role in Male Infertility

Sertoli cell-only syndrome (SCOS), also known as germ cell aplasia, represents a severe form of non-obstructive azoospermia where seminiferous tubules contain only Sertoli cells and lack germ cells, leading to complete infertility. This condition arises from impaired spermatogonial proliferation or survival, resulting in the absence of spermatozoa production despite the presence of otherwise functional Sertoli cells. Genetic factors play a significant role, with Y-chromosome microdeletions in the azoospermia factor (AZF) regions, particularly AZFa, being a well-established cause in approximately 10-15% of cases, disrupting genes essential for germ cell development. Other genetic abnormalities, such as Klinefelter syndrome (47,XXY karyotype), can also manifest as SCOS by altering Sertoli cell-germ cell dynamics and leading to progressive germ cell loss.^[44]^[44]^[45] Endocrine disruptors, including phthalates commonly found in plastics and personal care products, contribute to male infertility by targeting Sertoli cell function and disrupting Sertoli-germ cell interactions. Exposure to phthalates, such as di(2-ethylhexyl) phthalate (DEHP), has been shown to reduce Sertoli cell proliferation, impair tight junction integrity, and decrease production of supportive factors like androgen-binding protein, ultimately leading to diminished sperm production and oligospermia or azoospermia. Animal studies demonstrate that prenatal or neonatal phthalate exposure alters Sertoli cell differentiation and steroidogenesis regulation, with human epidemiological data linking higher urinary phthalate metabolites to poorer semen quality and increased infertility risk.^[46]^[47]^[48] Elevated follicle-stimulating hormone (FSH) levels serve as a key biomarker for Sertoli cell impairment in male infertility, reflecting disrupted feedback mechanisms due to reduced inhibin B secretion from dysfunctional Sertoli cells. In conditions like SCOS, serum FSH is typically markedly elevated (>7.6 IU/mL), indicating primary testicular failure and poor spermatogenic reserve, which correlates with low success rates in sperm retrieval procedures. This biomarker helps differentiate Sertoli-related infertility from obstructive causes, guiding clinical management such as assisted reproductive technologies.^[44]^[49]^[50] Sertoli cell dysfunction is also implicated in cryptorchidism and varicocele, common conditions associated with male infertility through altered Sertoli-germ cell interactions. In cryptorchidism, undescended testes experience elevated temperatures that induce heat stress on Sertoli cells, impairing their ability to nurture germ cells and leading to reduced germ cell numbers and spermatogenic arrest. Similarly, varicocele, characterized by venous dilation in the pampiniform plexus, causes oxidative stress and hypoxia that disrupt Sertoli cell metabolism and junctional proteins, compromising germ cell adhesion and maturation, with studies showing improved fertility outcomes post-varicocelectomy in affected men.^[51]^[52]^[53]

Sertoli Cell Tumors and Disorders

Sertoli cell tumors are rare neoplasms originating from the gonadal stroma, specifically the Sertoli cells of the testis, accounting for approximately 1% of all testicular tumors.^[54] These tumors are typically benign and slow-growing, often presenting in young adults or adolescents with symptoms such as a painless testicular mass or gynecomastia due to excess estrogen production by the tumor cells.^[55] Gynecomastia occurs in about one-third of cases, resulting from the aromatization of androgens to estrogens within the neoplastic Sertoli cells.^[56] Sertoli cell adenomas, also known as classic Sertoli cell tumors, form well-circumscribed, lobulated masses with tubular or cord-like arrangements of cells resembling normal Sertoli cells.^[54] A distinctive subtype is the large cell calcifying Sertoli cell tumor (LCCSCT), characterized by large polygonal cells, intracellular or stromal calcifications, and Reinke-like crystalloids.^[57] LCCSCTs are frequently bilateral and multifocal, with up to 40% of cases linked to genetic syndromes; notably, germline mutations in the PRKAR1A gene underlie their association with Carney complex, an autosomal dominant disorder featuring myxomas, spotty pigmentation, and endocrine overactivity.^[58] Somatic PRKAR1A mutations can also occur in nonsyndromic cases, contributing to tumor development through dysregulation of protein kinase A signaling.^[59] In Peutz-Jeghers syndrome (PJS), an autosomal dominant condition caused by STK11 gene mutations, Sertoli cells exhibit diffuse intratubular involvement, often manifesting as large cell hyalinizing Sertoli cell neoplasia that is multifocal and bilateral.^[60] This leads to elevated estrogen levels and feminizing features like gynecomastia in affected males, with tumors typically non-invasive but increasing the risk of malignancy over time.^[57] Diagnosis of Sertoli cell tumors relies on a combination of clinical evaluation, imaging, and histopathological analysis. Ultrasound typically reveals a hypoechoic, well-defined intratesticular mass, while CT or MRI may assess for calcifications in LCCSCTs.^[54] Immunohistochemistry is crucial for confirmation, with strong positivity for inhibin (alpha-subunit) in over 90% of cases, alongside calretinin, steroidogenic factor-1 (SF-1), and WT-1, distinguishing these tumors from germ cell neoplasms or other stromal lesions.^[61]^[62]

Comparative and Evolutionary Biology

Sertoli Cells in Non-Human Animals

In rodents, such as mice and rats, Sertoli cells exhibit prolonged postnatal proliferation compared to humans, leading to higher overall numbers per testis and a greater proportion of Sertoli cells within seminiferous tubules (approximately 20% in immature rodents versus 3-5% in adult humans).^[63] This structural adaptation supports continuous spermatogenesis throughout the year, in contrast to the seasonal breeding patterns observed in many other mammals where Sertoli cell activity and germ cell production are cyclically suppressed during non-breeding periods.^[64]^[65] Avian Sertoli cells are organized within seminiferous cords or tubules that form lobules in the testis, with a rete testis connecting the tubules to efferent ducts to facilitate sperm transport in a compact structure differing from the mammalian configuration.^[64]^[66] This arrangement supports seasonal spermatogenesis in most birds, with Sertoli cells providing nourishment to germ cells in a radial orientation around the cord lumen, and the blood-testis barrier forming later in development than in mammals.^[67] In fish and amphibians, Sertoli cell homologs known as cyst cells encyst germ cells within testicular cysts, enabling a cystic mode of spermatogenesis distinct from the tubular system in higher vertebrates.^[64] These cyst cells are particularly influenced by temperature-dependent sex determination in species like the Nile tilapia, where elevated temperatures promote masculinization and enhance cyst cell proliferation to support testis development and sperm production.^[68]^[69] Sertoli cell tumors hold significant veterinary relevance in dogs, where they are common in older intact males and often hormone-responsive, secreting excess estrogen that induces hyperestrogenism syndrome in 25-50% of cases, manifesting as feminization, alopecia, and bone marrow suppression.^[64]^[70] These tumors disrupt normal Sertoli cell function, leading to elevated estradiol-17β levels and clinical signs that resolve post-surgical removal, underscoring their responsiveness to hormonal and therapeutic interventions.^[71]

Evolutionary Conservation

Sertoli cells share a deep homology with ovarian granulosa cells, both arising from a common bipotential lineage of somatic supporting cells in the developing gonad across vertebrates. This shared developmental origin positions them as counterparts in male and female gonads, respectively, where their differentiation defines gonadal sex. A key mechanism underlying this homology is the conserved antagonism between the transcription factors SOX9 and FOXL2, which regulates cell fate during sex determination and maintenance. In males, SOX9 drives Sertoli cell specification and testis differentiation, while FOXL2 promotes granulosa cell identity and ovarian development; mutual repression between these factors ensures robust sex-specific outcomes from the bipotential precursors.^[72]^[73]^[74] This SOX9-FOXL2 antagonism is phylogenetically conserved among vertebrates, operating similarly in diverse species from fish to mammals to stabilize gonadal identity post-determination. For instance, experimental ablation of FOXL2 in adult mammalian ovaries triggers SOX9 upregulation and granulosa-to-Sertoli transdifferentiation, highlighting the ongoing role of this regulatory network in preventing sex reversal. In non-mammalian vertebrates, analogous pathways reinforce SOX9's pro-male function during early gonadogenesis, underscoring the evolutionary stability of supporting cell fate decisions despite variations in upstream sex-determining triggers.^[75] The functional role of Sertoli-like cells in gonad differentiation traces back to ancient invertebrate ancestors, exemplified by somatic cyst cells in Drosophila melanogaster, which serve as homologs by enveloping and nurturing germ cells during spermatogenesis. These cyst cells originate from somatic gonadal precursors and regulate germ cell proliferation, cyst formation, and differentiation through signaling pathways like JAK/STAT and BMP, mirroring the supportive niche provided by vertebrate Sertoli cells. This homology indicates that the core mechanism of somatic-germ cell interactions evolved prior to the vertebrate-invertebrate divergence, with cyst cells representing a primitive analog that facilitated the transition to more complex gonadal structures in bilaterians.^[76]^[77] In jawed vertebrates (gnathostomes), the blood-gonad barrier—formed by specialized tight junctions between Sertoli cells—exhibits remarkable conservation, establishing immune privilege to protect meiotic and post-meiotic germ cells from autoimmune attack. This barrier first appears in teleost fish, where Sertoli cells form transient junctions around haploid germ cell cysts post-meiosis, preventing antigen exposure while allowing nutrient passage. Similar structures are evident in amphibians and reptiles, adapting to cystic or tubular testicular organization, and culminate in the continuous basal compartment barrier of mammals. The preservation of this feature across gnathostomes reflects an evolutionary adaptation to the immunogenic nature of haploid gametes, enabling spermatogenesis in an immunocompetent host without eliciting tolerance breakdown.^[78]^[79]^[80] Evolutionary adaptations in Sertoli cells further highlight their plasticity, particularly through polyploidization in select mammalian lineages, which enhances their capacity to support extensive spermatogenesis. In species like the rat, adult Sertoli cells undergo endoreplication to achieve polyploid nuclei (e.g., 4N or higher), increasing cell size, RNA content, and metabolic output without mitotic division. This adaptation compensates for the postnatal cessation of proliferation in mammals, allowing a single Sertoli cell to nurture more germ cells—up to 30-50 spermatids in rodents—compared to the lower ratios in species without pronounced polyploidy. By boosting synthetic machinery for proteins, hormones, and nutrients, polyploidy represents a derived mammalian strategy to optimize efficiency in non-cystic testes, contrasting with the high proliferative support in anamniote Sertoli cells.^[81]^[2]^[82]

Historical Discovery and Ongoing Research

Historical Milestones

The Sertoli cell was first described in 1865 by Italian physiologist Enrico Sertoli, who, at the age of 23, used light microscopy to observe branched, elongated cells within the seminiferous tubules of human testes, noting their potential supportive role in spermatogenesis.^[83] These structures, initially termed "special branched cells," were highlighted in Sertoli's publication in the journal Morgagni, marking the initial recognition of their distinct morphology and position enveloping developing germ cells.^[84] In 1888, Austrian anatomist Viktor von Ebner formally named these cells "Sertoli cells" in his histological studies, further emphasizing their sustentacular, or nursing, function in providing structural support and nourishment to germ cells during spermatogenesis.^[2] Early 20th-century research built on this by exploring their phagocytic activity; for instance, in 1901, French histologist Charles Regaud proposed that Sertoli cells engulf and degrade degenerating germ cells, reinforcing their protective and regulatory role in the testicular environment.^[84] A major advancement occurred in the 1960s with the identification of the blood-testis barrier (BTB), a critical structure formed by tight junctions between Sertoli cells that segregates the seminiferous epithelium into basal and adluminal compartments to protect meiotic and post-meiotic germ cells from immune surveillance. In 1967, physiologist Brian P. Setchell provided the first physiological evidence of the BTB through tracer studies in sheep, demonstrating restricted passage of substances into the adluminal compartment.^[2] This was complemented in 1970 by electron microscopy work from Marvin Dym and Don W. Fawcett, who ultrastructurally confirmed the barrier's location at Sertoli-Sertoli junctions, establishing its role in creating an immunoprivileged site essential for spermatogenesis.^[84] The 1970s saw the discovery of inhibin, a key hormone secreted by Sertoli cells to regulate follicle-stimulating hormone (FSH) production in the pituitary, thus providing negative feedback in the hypothalamic-pituitary-gonadal axis. Seminal experiments in 1978 by M. Chowdhury, A. Steinberger, and E. Steinberger demonstrated inhibin activity in Sertoli cell culture media from rats, linking it directly to FSH suppression.^[2] This was solidified in 1979 when A. Steinberger isolated and characterized inhibin production by cultured Sertoli cells, highlighting their endocrine function in reproductive homeostasis.^[85] By the 1990s, molecular genetics revealed the genetic basis for Sertoli cell specification during embryonic development. In 1990, Peter Koopman and colleagues identified the SRY gene on the Y chromosome as the primary sex-determining factor in mammals, showing its expression in pre-Sertoli cells initiates testis differentiation and Sertoli cell differentiation from gonadal bipotential cells.^[84] This discovery linked Sertoli cells to the core mechanism of male sex determination, integrating histological observations with genetic insights.^[2]

Current Research Frontiers

Recent advances in stem cell research have focused on differentiating induced pluripotent stem cells (iPSCs) into Sertoli-like cells to address male infertility, particularly in conditions like Sertoli cell-only syndrome. Post-2015 studies have demonstrated the potential of 3D culture systems, such as organoids, to mimic the gonadal niche and promote iPSC differentiation into functional Sertoli cells that support spermatogenesis in vitro. For instance, iPSC-derived Sertoli cells have shown the ability to form blood-testis barrier-like structures and secrete key factors like androgen-binding protein, offering promising models for infertility therapies. These developments build on earlier protocols but incorporate advanced biomaterials to enhance cell maturation and integration, with ongoing trials exploring their transplantation into animal models to restore fertility.^[86]^[87] CRISPR/Cas9 gene editing has emerged as a powerful tool to investigate Sertoli cell functions, particularly through targeted mutations in genes like DMRT1, which regulates male gonad development. Editing DMRT1 in animal models, such as rabbits and medaka fish, has revealed its essential role in preventing sex reversal, where loss of function leads to Sertoli cell transdifferentiation into ovarian-like granulosa cells and subsequent infertility. In mice, DMRT1 knockouts have been used to study post-pubertal sex reversal and the gene's tumor-suppressive effects in Sertoli cells, linking its dysregulation to testicular tumorigenesis. These CRISPR applications, advanced since the mid-2010s, provide insights into genetic therapies for disorders involving Sertoli cell dysfunction.^[88]^[89]^[90] Environmental toxicology research in the 2020s has highlighted the disruptive effects of microplastics on Sertoli cell function, with studies showing that polystyrene microplastics impair blood-testis barrier integrity and induce oxidative stress in both in vitro and in vivo models. Exposure to polyethylene microplastics has been linked to altered focal adhesion kinase signaling in Sertoli cells, reducing their metabolic activity and support for germ cells, potentially contributing to declining male fertility rates. Recent investigations, including those using rat and human Sertoli cell lines, demonstrate that nanoplastics exacerbate ferroptosis and inflammation, emphasizing the need for further epidemiological studies on human exposure.^[91]^[92]^[93] Therapeutic transplantation of Sertoli cells for immunosuppression has progressed from 2000s animal trials, where porcine or rodent Sertoli cells protected co-transplanted islets in diabetic models by creating local immune-privileged environments. Building on these, recent preclinical studies have explored Sertoli cell grafts in autoimmune disease models, such as multiple sclerosis, showing prolonged survival of neural cells due to secretion of immunomodulatory factors like TGF-β and Fas ligand. Encapsulated human Sertoli cells have demonstrated systemic tolerance induction in xenogeneic settings, reducing autoantibody responses without broad immunosuppression, paving the way for clinical translation in autoimmune disorders.^[94]^[95]^[96]

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