Sertoli cell

Sertoli cells are a type of

History

Sertoli cells are named after Enrico Sertoli, an Italian physiologist who discovered them while studying medicine at the University of Pavia, Italy.^[1] He published a description of his eponymous cell in 1865.^[2] The cell was discovered by Sertoli with a Belthle microscope which had been purchased in 1862. In the 1865 publication, his first description used the terms "tree-like cell" or "stringy cell"; most importantly, he referred to these as "mother cells". Other scientists later used Enrico's family name to label these cells in publications, beginning in 1888. As of 2006, two textbooks that are devoted specifically to the Sertoli cell have been published.

Structure

Sertoli cells are specifically located in the convolutions of the seminiferous tubules, since this is the only place in the testes where spermatozoa are produced. As the primary support cell of the tubules, they are generally very large and amorphous, with individual cells stretching from the basal lamina to the lumen; their cytoplasm often completely surrounds the germline cells which they are responsible for nursing. Sertoli cells are easily confused with the other cells of the germinal epithelium when using standard staining techniques; the most distinctive feature of the Sertoli cell is its dark nucleolus.^[3]

Development

Sertoli cells are required for male sexual development. Sertoli cell proliferation and differentiation is mainly activated by FGF9, with which they also form a feedforward loop.^[4][5] It has been suggested that Sertoli cells may derive from the fetal mesonephros.^[6] After puberty, Sertoli cells begin to elongate. Their nucleoli become larger and tight junctions are completed, creating a fluid-filled lumen space.^[7]

FSH is responsible for controlling the proliferation of Sertoli cells shortly after birth and stimulates the production of factors derived from Sertoli cells that control the development of the testes and germ cells. FSH, luteinizing hormone. thyroid-stimulating hormone, and hCG are all known to affect Sertoli cell development and male reproductive health. FSH is required for Sertoli cell mitogen, which stimulates the expression of various cell markers.^[7]

Once fully differentiated, the Sertoli cell is considered terminally differentiated, and is unable to proliferate.^[8] Therefore, once spermatogenesis has begun, no more Sertoli cells are created, and their population within the seminiferous tubules is finite.

Recently, however, scientists have found a way to induce Sertoli cells to a juvenile proliferative phenotype outside of the body.^[9] This gives rise to the possibility of repairing some defects of testicular niche cells which may cause male infertility.

Function

Because its main function is to nourish developing sperm cells through the stages of spermatogenesis, the Sertoli cell has also been called the "mother" or "nurse" cell.^[10] Sertoli cells also act as phagocytes, consuming the residual cytoplasm during spermatogenesis. Translocation of cells from the basal lamina 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
• activins, secreted after puberty, 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, an aromatase which converts testosterone to 1,7-beta-estradiol to direct spermatogenesis
• ETS Related Molecule or ERM transcription factor is needed for maintenance of the spermatogonial stem cells
  in the adult testis
• transferrin, a blood plasma protein for iron ion delivery^[11]
• testicular ceruloplasmin, a ceruloplasmin-like protein which is immunologically similar to serum ceruloplasmin.^[12]

Structural

The

Sertoli cells are capable of repairing DNA damage.^[14] This repair likely employs the process of non-homologous end joining involving XRCC1 and PARP1 proteins that are expressed in Sertoli cells.^[14]

Sertoli cells have a higher mutation frequency than spermatogenic cells.^[15] 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 also produce a wide range of molecules (either on their surface or soluble) that are able to modify the immune system. The ability of Sertoli cells to change the immune response in the tubule is needed for successful sperm cell maturation. Sperm cells express neo-epitopes on their surface as they progress through different stages of maturation, which can trigger a strong immune response if placed in a different part 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, e.g. cytotoxic T cells.^[16]

- 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 immune cells)

B7/H1 – decreasing proliferation of effector T-cells^[17]

Jagged1 (JAG1) – induction of Foxp3 transcription factor expression in naive T lymphocytes (increasing relative numbers of T regulatory cells)^[18]

Protease inhibitor-9 (PI-9) – member of serpin family (serine protease inhibitors),^[19] which induces secretion of protease Granzyme 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.

Clusterin, a soluble molecule with functions similar to CD59, forms a complex with Granzyme B and inhibits activation of apoptosis by T-lymphocytes or NK cells.[20]

TGF-beta, a transforming growth factor beta (its direct production by SCs is controversial), contributes to the induction of regulatory T-cells on the periphery.^[21]

Other molecules

CD40, a molecule associated with dendritic cells (DCs). SCs are able to down regulate the expression of CD40 on the surface of DCs, by an unknown mechanism. Downregulation of CD40 results in the decreased ability of DCs to stimulate the T-cell response.^[20]

Sertoli cells are also able to inhibit the migration of immune cells by lowering immune cell infiltration to the site of inflammation.

Clinical significance

The once commonly accepted fact that Sertoli cells are unable to divide and proliferate in Amniota has recently been challenged. Upon xenogenic transplantation, Sertoli cells have been shown to regain the ability to proliferate.[26]

Research

Recently (2016), experimental models of

• Sertoli cell-only syndrome
• Sertoli cell nodule
• List of distinct cell types in the adult human body

References

External links

Wikimedia Commons has media related to Sertoli cells.

• Histology image: 17805loa – Histology Learning System at Boston University
• Histology image: 17806loa – Histology Learning System at Boston University