Introduction

Sertoli cells are present in the seminiferous tubules of the male gonads, the testes. They were first observed in 1865 by a young Italian physician Enrico Sertoli and named after him.[1] Sertoli cells comprise one of the two types of cells in the germinal epithelium, the other being of spermatogonia lineage. Sertoli cells are one of the most important cells necessary for sperm production in males. They are often identifiable as big, tightly linked cells near the basolateral portion of the seminiferous tubule. They are also known as sustentacular cells of Sertoli and are the nursemaid cells of the primary spermatogonia.[2] See Illustration. Illustration of Histology of Testes. 

Sertoli cells help to facilitate the process of spermiogenesis, and thus the production of viable sperm. Sertoli cells also secrete a myriad of vital molecules, include androgen binding protein (ABP), Inhibin B, and Activin. These secretions facilitate spermatogenesis directly or indirectly via a hormonal negative feedback system. Sertoli cells also respond to pituitary hormones such as follicle-stimulating hormone (FSH) to begin the process of spermatogenesis, supplementing the adjacent spermatogonia.[3][4][5] Sertoli cells are so important that their mere absence in testes can lead to infertility in adult males even though the production of sperms is normal.[6]

Issues of Concern

During the development and differentiation of Sertoli cells from their supporting cell precursors in the genital ridge, an autosomal gene known as the SOX9 (SRY-Box Transcription Factor 9) is very much essential.  Apart from the sex-determining region of the Y chromosome (SRY), the steroidogenic factor 1 (NR5A1) also helps in the differentiation of the Sertoli cells.

The absence of these factors will result in the formation of female gonads, the ovaries. Upon reaching the essential levels of SRY and SOX9, the gonads start demonstrating morphological changes to a true testis. These changes include the epithelization of the Sertoli cells, differentiation of Leydig and myoid cells, testicular cords formation, and mitotic arrest of germ cells.[7]

Structure

Sertoli cells are the biggest, non-uniformly shaped cells of the germinal epithelium in the seminiferous tubules. They are most reliably identified by always being the largest columnar cell that is still attached to the basal lamina of the basement membrane, and span to the apical lumen of the cross-sectioned seminiferous tubule. They are often irregular, or pyramidal-shaped, but will always be towards the basolateral side, as opposed to the secondary spermatogonia and spermatids towards the lumen. The Sertoli cells can be differentiated from the nearby primary spermatogonia. Primary spermatogonia often have darker distinct nuclei in a small circular uniform cell, as opposed to Sertoli cells having more paler nuclei in a larger, irregularly shaped cell.[3][8]

It is important to note that the Sertoli cell structure forms tight junctions and connective adhesion molecules with neighboring Sertoli cells so that there can be local sequestering of testosterone. This junction is the basis of the blood-testes-barrier, which provides many necessary conditions for appropriate spermatogenesis, including ion regulation, testosterone concentration, immune system evasion, and barrier protection. The Sertoli cells form the inner perimeter of the cross-sectioned seminiferous tubule, with the germ cell epithelium being the only other most exterior cellular structures, resulting in mature spermatogonia and spermatids being interior to the Sertoli cell blood-testes-barrier.[8][9]

Function

Sertoli cells play many roles and have many functions within the seminiferous tubules. One of the most important features is to secrete a compound called Mullerian Inhibiting Factor, which helps to prevent the development of female sex organs following the determining of the testes embryologically. Sertoli cells also secrete Inhibin B, which helps to regulate FSH by acting on the anterior pituitary. Sertoli cells aid in concentrating the testosterone available by secreting a substance called androgen binding protein. Sertoli cells also maintain optimal health conditions for the primary spermatogonia and spermatogenesis process by regulating the ions, amino acids, and ultimately “nursing” the spermatogonia. The Sertoli cell overall is paramount to the spermatogenesis process and regulates this process via FSH receptor stimulation from the anterior pituitary. In the final process of spermiogenesis, which is the last step of spermatid maturation, the Sertoli cells function to degrade residual cytoplasm after it is shed from the spermatid.[9][10][11][12]

Structurally, the Sertoli cell has another outstanding job, which is to maintain the blood-testes-barrier. This barrier forms from tight junctions between adjacent Sertoli cells, which all sit on the basement membrane of the seminiferous tubules. This arrangement creates two useful layers of the seminiferous tubules. Interior to the tight junctions are the primary and secondary spermatogonia, as well as spermiogenesis. Exterior to the tight junction are germinal epithelial cells, and primitive spermatogonia. This barrier is also essential to allow for conditions to be capable of sequestering testosterone and increase local concentrations necessary for spermatogenesis. The blood-testes-barrier also serves to help evade auto-immune diseases or any surveillance by the body’s immune system.[10][13][14]

A summarization of Sertoli cell function is as follows:

1. They help in supporting, protecting and provide nutrition to spermatogenic cells[15][16]
2. Play a role in the paracrine and endocrine control of spermatogenesis[17]
3. Sertoli cells regulate cholesterol metabolism at the time of spermatogenesis.[7]
4. They help in the movement of spermatozoa by secreting fluids [18]
5. They phagocytose apoptotic cells, foreign bodies, etc.[19]
6. They secrete the androgen-binding protein under the influence of follicular stimulating hormone (FSH)[7]
7. Secret inhibin B hormone that suppresses the release of FSH [20]
8. Formation of a blood-testes barrier by tight junctions between them [7]

Histochemistry and Cytochemistry

In histochemistry, Sertoli cells stand out when stained for the androgen receptors. The androgen receptor is only on the nucleus of the Sertoli cell. Because of this, the androgen receptor can be reliably identified with the Sertoli cell. There are, however, other histochemistry and cytochemistry markers for which the Sertoli cell would also stain positively. These markers include SOX9, WT1, the GATA binding proteins, and many more. It is important to note that the SOX9 marker represents the SRY coded gene, and the WT1 gene represents a Wilms tumor.[21][9]

Microscopy, Light

Sertoli cell identification first starts with looking towards the basolateral aspect of the seminiferous tubules. One can observe that Sertoli cells are large irregularly shaped cells that form an inner perimeter, along with smaller more-uniformly-shaped-circular cells. These are the primary spermatogonia that the Sertoli cells will provide sustenance too. The Sertoli cell can also be identified by looking for the paler nucleus’ in comparison to its neighboring cell, the primary spermatogonia, who have much darker, rounder nuclei. There are also primitive spermatids resting over the apical end of the Sertoli cell, which will undergo spermiogenesis and bud off into the lumen of the seminiferous tubules.[21][9][22]

Microscopy, Electron

Under microscopy electron observation of Sertoli cells, one can observe that the nucleus is indented, which is often the identifying factor when scanning the basolateral aspect of the seminiferous tubules. Sertoli cells are the biggest and most asymmetrically shaped cells in the basolateral aspect. They can be further identified by their prominent larger nucleus, in comparison to the large volume of the cytoplasm of the Sertoli cell. The nucleus is oval-shaped and basal, with a prominent nucleolus. The developing spermatogenic cells in different stages indent all over the Sertoli cells. Up to 40 germ cells in different stages of differentiation are in contact with each Sertoli cell.[19]

The most primitive cells, like spermatogonia and spermatocytes, indent near the basement membrane. The more mature cells like spermatids indent near the apex of the Sertoli cells, towards the center of the lumen of the seminiferous tubules. Researchers have noted that Sertoli cells provide a phagocytic function to help remove cytoplasmic waste and debris from the seminiferous tubules and would be in vacuoles of the Sertoli cell. There are also often many layers of smooth endoplasmic reticulum surrounding the nucleus of the Sertoli cell, where the SER functions in lipid removal and processing. There can be many mitochondria observed as well, as the Sertoli cell needs ATP to be able to secrete and synthesize compounds such as Inhibin B, ABP, and Activin. There are two prominent DNA chromocenter satellites present as well, as they form connections with primitive spermatids and drawing the spermatids closer to the basolateral crypts of the Sertoli cell.[9][21][23]

Clinical Significance

Sertoli cell-only syndrome is a condition in which there is a complete absence of germ cells within the testes resulting in male infertility. It is seen mostly with Klinefelter syndrome and Yq microdeletions patients.[24]

In Klinefelter syndrome, a primary hypergonadotropic hypogonadism disorder is characterized by trisomy 47 XXY, and patients will present with very typical characteristics. These include gynecomastia, tall long extremities, a feminized body type, and lastly, dysfunction of the gonadal processes. Because there are no functional Leydig or Sertoli cells, there will be low testosterone levels due to lack of Leydig cells, and there will be no inhibin released by the Sertoli cells. Because there is no inhibin to shut down GnRH release, GnRH levels will typically be high, and this subsequently leads to high LH and FSH levels. It is important to note that testicular histology will often show fibrosis and connective tissue damage of the interstitial space and the seminiferous tubules.[25][26][27]

Sertoli cell pathology can also occur in Sertoli cell tumors or Sertoli-Leydig cell tumors. These are sex-cord-stromal cancers and can occur in men and women. However, Sertoli-Leydig cell tumors most commonly occur in the older women demographic. It is also essential to note that in patients with Sertoli-Leydig cell tumors, there will often be elevated hormone levels, such as increased androgens in Sertoli-Leydig tumors. This condition would present clinically as a significant painless mass in the ovaries or testes, and cause possible virilization, hirsutism, clitoromegaly, increased lean muscle mass, etc.[28][29][30]

A disruption in the normal development of the Sertoli cell results in a condition known as testicular dysgenesis syndrome. It is a condition in which the patient will have hypospadias, cryptorchidism, poor quality of semen, and going into testicular germ cell cancer.[31]