Sertoli cell

A Sertoli cell (a kind of sustentacular cell) is a "nurse" cell of the testicles that is part of a seminiferous tubule and helps in the process of spermatogenesis, the production of sperm.

Germinal epithelium of the testicle.
1: basal lamina
2: spermatogonia
3: spermatocyte 1st order
4: spermatocyte 2nd order
5: spermatid
6: mature spermatid
7: Sertoli cell
8: tight junction (blood testis barrier)
Histological section through testicular parenchyma of a boar.
1 Lumen of Tubulus seminiferus contortus
2 spermatids
3 spermatocytes
4 spermatogonia
5 Sertoli cell
6 Myofibroblasts
7 Leydig cells
8 capillaries
Details
SystemReproductive system
LocationTestes
FunctionAssist in the production of sperm
Identifiers
MeSHD012708
FMA72298
Anatomical terms of microanatomy

It is activated by follicle-stimulating hormone (FSH) secreted by the adenohypophysis, and has FSH receptor on its membranes. It is specifically located in the convoluted seminiferous tubules (since this is the only place in the testes where the spermatozoa are produced). Development of Sertoli cells is directed by the protein.

Structure

Sertoli cells are located in seminiferous tubules.

On slides, using standard staining, Sertoli cells can easily be confused with the other cells of the germinal epithelium. The most distinctive feature of the Sertoli cell is the dark nucleolus.[1]

Development

Sertoli cells are required for male sexual development. It activates and forms a feedforward loop with FGF9. Sertoli cell proliferation and differentiation is mainly activated by FGF9.[2] [3]

Once fully differentiated, the Sertoli cell has been considered to be terminally differentiated, and is unable to proliferate.[4] Therefore, once spermatogenesis has begun, no more Sertoli cells are created.

Recently however, some scientists have found a way to induce Sertoli cells to a juvenile proliferative phenotype outside of the body.[5] This gives rise to the possibility of repairing some defects that cause male infertility.

It has been suggested that Sertoli cells may derive from the fetal mesonephros.[6]

Function

Because its main function is to nourish the developing sperm cells through the stages of spermatogenesis, the Sertoli cell has also been called the "mother" or "nurse" cell.[7] Sertoli cells also act as phagocytes, consuming the residual cytoplasm during spermatogenesis. Translocation of cells from the base to the lumen of the seminiferous tubules occurs by conformational changes in the lateral margins of the Sertoli cells.

Secretory

Sertoli cells secrete the following substances:

  • anti-Müllerian hormone (AMH) — secreted during the early stages of fetal life.
  • inhibin and activins  — secreted after puberty, and work together to regulate FSH secretion.
  • androgen binding protein (also called testosterone binding globulin) — increases testosterone concentration in the seminiferous tubules to lightly stimulate spermatogenesis.
  • estradiol — aromatase from Sertoli cells convert testosterone to 17 beta estradiol to direct spermatogenesis
  • ETS Related Molecule or ERM transcription factor ERM transcription factor — needed for maintenance of the spermatogonial stem cell in the adult testis.
  • transferrin — a blood plasma protein for iron ion delivery[8]
  • Testicular ceruloplasmin — a ceruloplasmin-like protein which is immunologically similar to serum ceruloplasmin[9]

Structural

The occluding junctions of Sertoli cells form the blood-testis barrier, a structure that partitions the interstitial blood compartment of the testis from the adluminal compartment of the seminiferous tubules. Because of the apical progression of the spermatogonia (sperm stem cells), the occluding junctions must be dynamically reformed and broken to allow the immunoidentical spermatogonia to cross through the blood-testis barrier so they can become immunologically unique. Sertoli cells control the entry and exit of nutrients, hormones and other chemicals into the tubules of the testis as well as make the adluminal compartment an immune-privileged site.

The cell is also responsible for establishing and maintaining the spermatogonial stem cell niche, which ensures the renewal of stem cells and the differentiation of spermatogonia into mature germ that progress stepwise through the long process of spermatogenesis, ending in the release of spermatozoa in a process known as spermiation.[10] Sertoli cells bind to spermatogonial cells via N-cadherins and galactosyltransferase (via carbohydrate residues).

Other functions

During spermatogenesis sertoli cells provide nutrition to the spermatogonia.

DNA repair and mutation

Sertoli cells are capable of repairing DNA damage.[11] This repair likely employs the process of non-homologous end joining involving XRCC1 and PARP1 proteins that are expressed in Sertoli cells.[11]

Sertoli cells have a higher mutation frequency than spermatogenic cells.[12] Compared to spermatocytes, the mutation frequency is about 5 to 10-fold higher in Sertoli cells. This may reflect the need for greater efficiency of DNA repair and mutation avoidance in the germ line than in somatic cells.

Immunomodulatory properties of Sertoli cells

Besides expressing factors that are crucial for sperm cell maturation, Sertoli cells are producing a wide range of molecules (either on their surface or soluble) that are able to modify the Immune system (IS). The ability of Sertoli cells to change the immune response in the tubule is needed for successful sperm cell maturation. Sperm cells are expressing neoepitopes on their surface as they progress through different stages of maturation. They can trigger a strong immune response if placed in a different site of the body.

Molecules produced by Sertoli cells associated with immunosuppression or immunoregulation

FAS/FAS-L system – expression of Fas ligand (Fas-L) on the surface of SCs activates apoptotic death of Fas receptor bearing cells, f.e. cytotoxic T-cells.[13]

- soluble FasL- increasing the effectivity of the system

- soluble Fas- FasL blockage on the surface of other cells ( no apoptotic induction in Sertoli cells by cells of IS)

B7/H1 – decreasing proliferation of effector T-cells[14]

Jagged1 (JAG1) – induction of Foxp3 transcription factor expression in naive T lymphocytes (increasing relative numbers of T regulatory cells)[15]

Protease inhibitor-9 (PI-9) – member of serpin family (serine protease inhibitors)[16]

- induces secretion of protease Granyzme B, cytotoxic T-cells and NK cells are able to induce apoptosis in target cell. SCs produce PI-9 that irreversibly bonds Granzyme B and inhibits its activity

CD59 - surface molecule on SCs, member of the Complement Regulatory Proteins (CRP)

- inhibits the last step of complement cascade – formation of the Membrane Atack Complex[17]

Clusterin – a soluble molecule, function similar to CD59 – making complex with Granyzme B and inhibits activation of apoptosis by T-lymphocytes or NK cells[17]

TGF-beta – transforming growth factor beta (its direct production by SCs is controversial)

- induction of regulatory T-cells in periphery[18]

Another molecules involved

CD40 - molecule associated with Dendritic Cells (DC)

- SCs are able to down regulate the expression of CD40 on the surface of DCs (mechanism not known)

- Downregulation of CD40 results in decreased ability of DCs to stimulate the T-cell response[17]

Sertoli cells are also able to inhibit the migration of immune cells – lower immune cells infiltration to the site of inflammation.

Clinical significance

Sertoli-Leydig cell tumour is part of the sex cord-stromal tumour group of ovarian neoplasms. These tumors produce both Sertoli and Leydig cells and lead to an increased secretion of testosterone in ovaries and testicles.

Other animals

Function of Sertoli cells in amniota and anamniota is the same, but they have a slightly different properties when compared to each other. Anamnionts (fish and amphibians) are employing cystic spermatogenesis in order to produce sperm cells.[19] In case of amniota Sertoli cells are considered to be terminally differentiated cells not able to proliferate. In anamniota Sertoli cells go through two proliferative phases. First phase of proliferation occurs during cyst establishment promoting also migration of germ cells into it.[20][21] second one is to enlarge the cyst and produce a space for proliferating germ cells.[22]

Commonly accepted fact that Sertol cells are terminally differentiated in amniota was recently changed. After xenogeneic transplantation Sertoli cells were able to proliferate.[23]

History

Sertoli cells are called so because of their eponym Enrico Sertoli, an Italian physiologist who discovered them while studying medicine in the University of Pavia, Italy.[24]

He published a description of this cell in 1865. The cell was discovered by Sertoli with a Belthle microscope purchased in 1862, which he used while studying medicine.

In the 1865 publication, his first description used the terms "tree-like cell" or "stringy cell" and most importantly he referred to these as "mother cells". It was other scientists who used Enrico's family name, Sertoli, to label these cell in publications, starting in 1888. As of 2006, two textbooks that are devoted specifically to the Sertoli cell have been published.

Research

Recently (2016), experimental models of autoimmune inflammatory disorders, including diabetes, have prompted the implication of Sertoli cells into cell therapy transplantation thanks to their immunoregulatory and anti-inflammatory properties.[25]

Research adopting Sertoli cells in Diabetes type I. treatment is in the deepest stage by now. The strategy is to cotransplant β cells together with Sertoli cells into recipient organism. In case of mice, rats and also human presence of these cells restored glucose homeostasis together with lower requirement of external insulin. In all cases no immunosuppression was used, the role of this medication was taken and provided by SC.[26][27][28]

By treating spontaneously diabetic and obese mice with the transplantation of microencapsulated Sertoli cells in the subcutaneous abdominal fat depot, Giovanni et al.[25] have demonstrated that more than the half of the treated mice showed improved glucose homeostasis. This recent scientific work promises a future better treatment to patients with type 2 diabetes mellitus through the use of cell therapy.

Sertoli cells promote skin graft acceptation by recipient organism[29] and also their presence helps to increase numbers of motor neurons in spinal cord of SOD1 mice (mouse model of Amyotrofic lateral sclerosis)[30]

Additional images
  • section of a tubule of the testis of a rat. X 250.

See also

References
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