Sertoli cells are a type of sustentacular "nurse" cell found in human testes which contribute to the process of

spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the t ...

(the production of sperm) as a structural component of the seminiferous tubules. They are activated by

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH) secreted by the adenohypophysis and express FSH receptor on their membranes.

History

Sertoli cells are named after Enrico Sertoli, an Italian physiologist who discovered them while studying medicine at the University of Pavia, Italy. He published a description of his eponymous cell in 1865. 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 Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in ...

techniques; the most distinctive feature of the Sertoli cell is its dark

nucleolus The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of s ...

Development

Sertoli cells are required for male sexual development. Sertoli cell

proliferation Proliferation may refer to: Weapons *Nuclear proliferation, the spread of nuclear weapons, material, and technology *Chemical weapon proliferation, the spread of chemical weapons, material, and technology * Small arms proliferation, the spread of ...

and differentiation is mainly activated by

FGF9 Glia-activating factor is a protein that in humans is encoded by the ''FGF9'' gene. Function The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell surviva ...

, with which they also form a feedforward loop. It has been suggested that Sertoli cells may derive from the fetal mesonephros. Once fully differentiated, the Sertoli cell is considered terminally differentiated, and is unable to proliferate. 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. 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

, the Sertoli cell has also been called the "mother" or "nurse" cell. Sertoli cells also act as

phagocyte Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek ', "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek ...

s, 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 * inhibin and

activin Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1986, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual ...

s, 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 Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development o ...

, an aromatase which converts

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteris ...

to 1,7-beta-estradiol to direct

* ETS Related Molecule or ERM transcription factor is needed for maintenance of the

spermatogonial stem cell A spermatogonial stem cell (SSC), also known as a type A spermatogonium, is a spermatogonium that does not differentiate into a spermatocyte, a precursor of sperm cells. Instead, they continue dividing into other spermatogonia or remain dormant ...

s in the adult testis *

transferrin Transferrins are glycoproteins found in vertebrates which bind to and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe3+ ions. Human transferrin is encoded ...

, a blood plasma protein for iron ion delivery * testicular ceruloplasmin, a

ceruloplasmin Ceruloplasmin (or caeruloplasmin) is a ferroxidase enzyme that in humans is encoded by the ''CP'' gene. Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1 ...

-like protein which is immunologically similar to serum ceruloplasmin.

Structural

The

occluding junction Tight junctions, also known as occluding junctions or ''zonulae occludentes'' (singular, ''zonula occludens''), are multiprotein Cell junction, junctional complexes whose canonical function is to prevent leakage of solutes and water and seals bet ...

s of Sertoli cells form the blood-testis barrier, a structure that partitions the interstitial

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in th ...

compartment of the testis from the adluminal compartment of the seminiferous tubules. Because of the apical progression of the

spermatogonia A spermatogonium (plural: ''spermatogonia'') is an undifferentiated male germ cell. Spermatogonia undergo spermatogenesis to form mature spermatozoa in the seminiferous tubules of the testis. There are three subtypes of spermatogonia in humans: ...

, the occluding junctions must be dynamically reformed and broken to allow the immunoidentical spermatogonia to cross through the blood-testis barrier so that they can become immunologically unique. Sertoli cells control the entry and exit of

nutrient A nutrient is a substance used by an organism to survive, grow, and reproduce. The requirement for dietary nutrient intake applies to animals, plants, fungi, and protists. Nutrients can be incorporated into cells for metabolic purposes or excr ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

s, and other chemicals into the tubules of the testis as well as make the adluminal compartment an immune-privileged site. Sertoli cells are also responsible for establishing and maintaining the

niche, which ensures the renewal of stem cells and the differentiation of

into mature germ cells that progress stepwise through the long process of spermatogenesis, ending in the release of

spermatozoa A spermatozoon (; also spelled spermatozoön; ; ) is a motile sperm cell (biology), cell, or moving form of the ploidy, haploid cell (biology), cell that is the male gamete. A spermatozoon Fertilization, joins an ovum to form a zygote. (A zygote ...

in a process known as spermiation. Sertoli cells bind to spermatogonial cells via

N-cadherin Cadherin-2 also known as Neural cadherin (N-cadherin), is a protein that in humans is encoded by the ''CDH2'' gene. CDH2 has also been designated as CD325 (cluster of differentiation 325). Cadherin-2 is a transmembrane protein expressed in multip ...

s and galactosyltransferase (via carbohydrate residues).

Other functions

During spermatogenesis, Sertoli cells provide nutrition to the spermatogonia. Sertoli cells are capable of repairing

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...

. This repair likely employs the process of

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...

involving XRCC1 and PARP1 proteins that are expressed in Sertoli cells. Sertoli cells have a higher mutation frequency than spermatogenic cells. 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 cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...

s. - 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 Jagged1 (JAG1) – induction of Foxp3 transcription factor expression in naive T lymphocytes (increasing relative numbers of

T regulatory cells T, or t, is the twentieth letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''tee'' (pronounced ), plural ''tees''. It is deri ...

) Protease inhibitor-9 (PI-9) – member of serpin family (serine protease inhibitors), 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. CD59, a surface molecule on SCs and a member of the

complement regulatory protein A complement is something that completes something else. Complement may refer specifically to: The arts * Complement (music), an interval that, when added to another, spans an octave ** Aggregate complementation, the separation of pitch-clas ...

s (CRP), inhibits the last step of the complement cascade, the formation of the membrane attack complex. 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. 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.

Other molecules

CD40, a molecule associated with

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...

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

Clinical significance

Sertoli-Leydig cell tumour is part of the

sex cord-stromal tumour Sex is the trait that determines whether a sexually reproducing animal or plant produces male or female gametes. Male plants and animals produce smaller mobile gametes (spermatozoa, sperm, pollen), while females produce larger ones (ova, oft ...

group of

ovarian neoplasm The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. T ...

s. These tumors produce both Sertoli and Leydig cells and lead to an increased secretion of testosterone in ovaries and testicles.

Other animals

The function of Sertoli cells in the Amniota and

Anamniota The anamniotes are an informal group of craniates comprising all fishes and amphibians, which lay their eggs in aquatic environments. They are distinguished from the amniotes (reptiles, birds and mammals), which can reproduce on dry land either by ...

is the same, but they have slightly different properties when compared to each other. Anamnionts (fish and amphibians) employ cystic spermatogenesis in order to produce sperm cells. In the Amniota, Sertoli cells are terminally differentiated cells which are normally incapable of proliferating. In the Anamniota, Sertoli cells go through two proliferative phases. The first phase of proliferation occurs during cyst establishment, promoting the migration of germ cells into it. The second phase involves enlargement of the cyst which produces space for the proliferating germ cells. 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.

Research

Recently (2016), experimental models of

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...

inflammatory disorders, including

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

, have prompted the implication of Sertoli cells into cell therapy transplantation thanks to their immunoregulatory and anti-inflammatory properties. Research into adapting Sertoli cells for use in the treatment of

type I diabetes mellitus Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin (beta cells) are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for ...

involves the strategy of cotransplanting β cells together with Sertoli cells into the recipient organism. In mice, rats, and humans, the presence of these cells restored

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, usi ...

homeostasis as well as lowered requirements for external

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabol ...

. In all cases no immunosuppression was used, and the role of this medication was taken and provided by SC. By treating spontaneously diabetic and obese mice with the transplantation of microencapsulated Sertoli cells in subcutaneous abdominal fat deposits, Giovanni ''et al.'' demonstrated that more than 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 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination ...

through the use of cell therapy. Sertoli cells promote skin graft acceptance by the recipient organism and their presence also helps to increase the numbers of motor neurons in the spinal cord of SOD1 mice (a mouse model used in the study of

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

References

External links

* * {{DEFAULTSORT:Sertoli Cell Human cells Barrier cells Testicle Protein secreting cells Scrotum