Sertoli cell

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Sertoli cell
Germinal epithelium testicle.svg
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)
Testicle-histology-boar-2.jpg
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
Identifiers
MeSH D012708
Anatomical terminology

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.

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 testis-determining factor protein.

Functions[edit]

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.[1] 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[edit]

Sertoli cells secrete the following substances:

Structural[edit]

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.[3] Sertoli cells bind to spermatogonial cells via N-cadherins and galactosyltransferase (via carbohydrate residues).

Other functions[edit]

During the maturation phase of spermiogenesis, the Sertoli cells consume the unneeded portions of the spermatozoa.

DNA repair and mutation[edit]

Sertoli cells are capable of repairing DNA damage.[4] This repair likely employs the process of non-homologous end joining involving XRCC1 and PARP1 proteins that are expressed in Sertoli cells.[5] 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[edit]

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 immunosupression or immunoregulation[edit]

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.[6]

- 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[7]

Jagged1 (JAG1) – induction of Foxp3 transcription factor expression in naive T lymphocytes (increasing relative numbers of T regulatory cells)[8]

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

- 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 inreversibely 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[10]

Clusterin – a soluble molecule, function similar to CD59 – making complex with Granyzme B and inhibits activation of apoptosis by T-lymphocytes or NK cells[10]

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

- induction of regulatory T-cells in periphery[11]

Another molecules involved[edit]

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[10]

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

Production of Sertoli cells[edit]

Sertoli cells are required for male sexual development. During male development, the gene SRY activates SOX9, which then activates and forms a feedforward loop with FGF9. Sertoli cell proliferation and differentiation is mainly activated by FGF9.[12] The absence of FGF9 tends to cause a female to develop[13]

Once fully differentiated, the Sertoli cell has been considered to be terminally differentiated, and is unable to proliferate.[14] 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.[15] 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.[16]

Nomenclature[edit]

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.[17]

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.

Histology[edit]

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.[18]

Pathology[edit]

Sertoli-Leydig cell tumour is part of the sex cord-stromal tumour group of ovarian neoplasms.

Additional images[edit]

Research[edit]

Recently, 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.[19] By treating spontaneously diabetic and obese mice with the transplantation of microencapsulated Sertoli cells in the subcutaneous abdominal fat depot, Giovanni et al.[19] 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.

See also[edit]

References[edit]

  1. ^ Rato, Luís; Alves, Marco G.; Socorro, Sílvia; Duarte, Ana I.; Cavaco, José E.; Oliveira, Pedro F. (1 May 2012). "Metabolic regulation is important for spermatogenesis". Nature Reviews Urology. 9 (6): 330–338. doi:10.1038/nrurol.2012.77. PMID 22549313. 
  2. ^ Xiong X, Wang A, Liu G, Liu H, Wang C, Xia T, Chen X, Yang K (2006). "Effects of p,p'-dichlorodiphenyldichloroethylene on the expressions of transferrin and androgen-binding protein in rat Sertoli cells". Environ Res. 101 (3): 334–9. doi:10.1016/j.envres.2005.11.003. PMID 16380112. 
  3. ^ O'Donnell, Liza; Nicholls, Peter K.; O’Bryan, Moira K.; McLachlan, Robert I.; Stanton, Peter G. (2011). "Spermiation". Spermatogenesis. 1 (1): 14–35. doi:10.4161/spmg.1.1.14525. PMC 3158646Freely accessible. PMID 21866274. 
  4. ^ Ahmed EA, Barten-van Rijbroek AD, Kal HB, Sadri-Ardekani H, Mizrak SC, van Pelt AM, de Rooij DG (2009). "Proliferative activity in vitro and DNA repair indicate that adult mouse and human Sertoli cells are not terminally differentiated, quiescent cells". Biol. Reprod. 80 (6): 1084–91. doi:10.1095/biolreprod.108.071662. PMID 19164176. 
  5. ^ Walter CA, Intano GW, McCarrey JR, McMahan CA, Walter RB (1998). "Mutation frequency declines during spermatogenesis in young mice but increases in old mice". Proc. Natl. Acad. Sci. U.S.A. 95 (17): 10015–9. doi:10.1073/pnas.95.17.10015. PMC 21453Freely accessible. PMID 9707592. 
  6. ^ Dal Secco, Valentina; Riccioli, Anna; Padula, Fabrizio; Ziparo, Elio; Filippini, Antonio (2008-02-01). "Mouse Sertoli Cells Display Phenotypical and Functional Traits of Antigen-Presenting Cells in Response to Interferon Gamma". Biology of Reproduction. 78 (2): 234–242. doi:10.1095/biolreprod.107.063578. ISSN 0006-3363. 
  7. ^ Kaur, Gurvinder; Thompson, Lea Ann; Dufour, Jannette M. "Sertoli cells – Immunological sentinels of spermatogenesis". Seminars in Cell & Developmental Biology. 30: 36–44. doi:10.1016/j.semcdb.2014.02.011. PMC 4043859Freely accessible. 
  8. ^ Campese, Antonio Francesco; Grazioli, Paola; de Cesaris, Paola; Riccioli, Anna; Bellavia, Diana; Pelullo, Maria; Padula, Fabrizio; Noce, Claudia; Verkhovskaia, Sofia (2014-03-01). "Mouse Sertoli Cells Sustain De Novo Generation of Regulatory T Cells by Triggering the Notch Pathway Through Soluble JAGGED1". Biology of Reproduction. 90 (3). doi:10.1095/biolreprod.113.113803. ISSN 0006-3363. 
  9. ^ Potempa, J.; Korzus, E.; Travis, J. (1994-06-10). "The serpin superfamily of proteinase inhibitors: structure, function, and regulation". The Journal of Biological Chemistry. 269 (23): 15957–15960. ISSN 0021-9258. PMID 8206889. 
  10. ^ a b c Lee, Hak-Mo; Oh, Byoung Chol; Lim, Dong-Pyo; Lee, Dong-Sup; Lim, Hong-Gook; Park, Chun Soo; Lee, Jeong Ryul (June 2008). "Mechanism of Humoral and Cellular Immune Modulation Provided by Porcine Sertoli Cells". Journal of Korean Medical Science. 23 (3): 514–520. doi:10.3346/jkms.2008.23.3.514. ISSN 1011-8934. PMC 2526533Freely accessible. PMID 18583891. 
  11. ^ Iliadou, Paschalia K.; Tsametis, Christos; Kaprara, Athina; Papadimas, Ioannis; Goulis, Dimitrios G. (October 2015). "The Sertoli cell: Novel clinical potentiality". Hormones (Athens, Greece). 14 (4): 504–514. doi:10.14310/horm.2002.1648. ISSN 2520-8721. PMID 26859601. 
  12. ^ Kim, Y.; Kobayashi, A.; Sekido, R.; Dinapoli, L.; Brennan, J.; Chaboissier, M. C.; Poulat, F.; Behringer, R. R.; Lovell-Badge, R.; Capel, B. (2006). "Fgf9 and Wnt4 Act as Antagonistic Signals to Regulate Mammalian Sex Determination". PLoS Biology. 4 (6): e187. doi:10.1371/journal.pbio.0040187. PMC 1463023Freely accessible. PMID 16700629. 
  13. ^ Moniot, Brigitte; Declosmenil, Faustine; Barrionuevo, Francisco; Scherer, Gerd; Aritake, Kosuke; Malki, Safia; Marzi, Laetitia; Cohen-Solal, Ann; Georg, Ina; Klattig, Jürgen; Englert, Christoph; Kim, Yuna; Capel, Blanche; Eguchi, Naomi; Urade, Yoshihiro; Boizet-Bonhoure, Brigitte; Poulat, Francis (2009). "The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation". Development. The Company of Biologists Ltd. 136 (11): 1813–1821. doi:10.1242/dev.032631. PMC 4075598Freely accessible. PMID 19429785. 
  14. ^ Sharpe, R. M.; McKinnell, C; Kivlin, C; Fisher, J. S. (2003). "Proliferation and functional maturation of Sertoli cells, and their relevance to disorders of testis function in adulthood". Reproduction (Cambridge, England). 125 (6): 769–84. doi:10.1530/reprod/125.6.769. PMID 12773099. 
  15. ^ Nicholls, P. K.; Stanton, P. G.; Chen, J. L.; Olcorn, J. S.; Haverfield, J. T.; Qian, H; Walton, K. L.; Gregorevic, P; Harrison, C. A. (2012). "Activin signaling regulates Sertoli cell differentiation and function". Endocrinology. 153 (12): 6065–77. doi:10.1210/en.2012-1821. PMID 23117933. 
  16. ^ Peter D. Vize; Adrian S. Woolf; Jonathan Bard (2003). The kidney: from normal development to congenital disease. Academic Press. pp. 82–. ISBN 978-0-12-722441-1. Retrieved 18 November 2010. 
  17. ^ synd/518 at Who Named It?
  18. ^ OSU Center for Veterinary Health Sciences - OSU-CVHS Home Archived 2006-12-09 at the Wayback Machine.[full citation needed]
  19. ^ a b Luca, Giovanni; Arato, Iva; Mancuso, Francesca; Calvitti, Mario; Falabella, Giulia; Murdolo, Giuseppe; Basta, Giuseppe; Cameron, Don F.; Hansen, Barbara C. (November 2016). "Xenograft of microencapsulated Sertoli cells restores glucose homeostasis in db/db mice with spontaneous diabetes mellitus". Xenotransplantation. 23 (6): 429–439. doi:10.1111/xen.12274. ISSN 1399-3089. PMID 27678013. 

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