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Location
Folliculostellate (FS) cells are located within the anterior lobe of the pituitary gland. They are located along with 5 types of endocrine cells involved in functions such as growth, metabolism and regulation.

Histology
The characteristic features of FS cells are their star shape, hence the –stellate part of the name, and their ability to form follicles. Unlike the majority of cells in the anterior pituitary, they are non-endocrine and agranular. They typically have a large number of microvilli on their apical side, and lysosomes exist within them, perhaps suggesting phagocytotic activity. Markers for FS cells include the S-100 protein, the Glial Fibriliary acidic protein (GFAP) and a more recent discovery, green florescent protein (GFP) which was found in the anterior pituitary of transgenic rats. The S-100 protein can also be found in the cells of Rathke’s pouch, suggesting a similarity between these cells.

Ultrastructure
Usually found lining the lumen of small follicles situated within the pituitary gland. They have long, cytoplasmic processes which interlock to form a mesh, within which the endocrine cells reside. Upon electron microscopy, gap junctions can be seen between the FS cells and the adjacent endocrine cells. They are excitable cells, something which is unusual given the fact that they are agranular.

Gap junctions between endocrine cells and FS cells
Despite FS cells lacking hormonal properties themselves, they influence the functionality of hormone-secreting endocrine cells via gap junctions. FS cells form homologous gap junctions with their adjacent counterparts, but also heterologous gap junctions with hormone-secreting endocrine cells. The gap junctions that exist between adjacent FS cells are used to propagate calcium-mediated signals throughout the pituitary to coordinate the function of excitable endocrine cells distributed throughout the gland. The endocrine-FS cell gap junctions, alongside the FS-FS gap junctions form a cell network that allows information about the physiological environment to be transferred around the pituitary to coordinate its secretory function.

Studies in various small mammals have demonstrated that the number of gap junctions is influenced by several factors, such as puberty, the menstrual cycle and lactation. In the mink, the presence of the connexon-43 protein that is functional in gap junctions, correlates to prolactin secretory demand depending on the breeding season. When prolactin secretion is highest in the spring there is the highest abundance of connexon-43 gap junctions; prolactin secretion and gap junctions are lowest in the winter. Thus demonstrating that the FS-cell network has a role in influencing prolactin secretion. This is consistent with studies in rats which found that gap junctions increased during lactation to facilitate prolactin demand. Additional studies in rats found that the number of gap junctions increases with anterior pituitary maturation, and this increase was prevented by castration in male rats which would prevent sexual maturation, and was restored to normal levels by hormone treatment. Similarly, gap junctions increase during pro-oestrus and oestrus phases of the menstrual cycle, and are decreased by fifty percent during di-oestrus. Evidently, the number of gap junctions is influenced by steroid hormone secretion from the gonads, and FS cells contribute to the pituitary-gonadal feedback loop.

Development and Markers Expressed
Rinehart and Farquhar first discovered follicullostellate (FS) cells through electron microscopy of the anterior pituitary gland. Initially these cells were thought to be corticotrophs, but are now described as adrenocorticotroph-like cells without the secretory element. Due to their follicle formation and stellate-like appearance, Vila-Porcile named these non-endocrine cells folliculo-stellate cells in 1972.

These non-hormone secreting cells are thought to act as supporting cells of the pituitary endocrine cells. It is clear that they do not just have a structural role though, because they have similar properties to dendritic cells and macrophages, implying a phagocytic role. FS cells also produce multiple different growth factors and cytokines, such as basic fibroblast growth factor (bFGF), follistatin, leukemia inhibitory factor (LIF) and interleukin 6.

Due to the unclear role of these non-hormone secreting cells, experiments have been carried out to assess the markers they express, in order to determine their cell-type and thus exact function in the pituitary. Due to their non-endocrine properties, studying these cells is much harder because simple immunohistochemistry using an antibody against a particular hormone cannot be used. The first marker protein discovered in these FS cells was S-100b, which is a calcium-binding protein expressed by glial cells. Discovering the S-100b protein marker made it much easier to visualise these cells under a light microscope.

Although the main marker is S100 protein, some populations of FS cells have also been found to express different cell markers, including GFAP (glial fibrillary acidic protein), cytokeratins, vimentin and fibronectin. S-100 protein and GFAP expression seem to be strongest in early, newly – formed FS cells, thus could be important in early FS cell development. GFAP expression implies these cells could be of a neuroectodermal origin, whereas keratin-positive FS cells express epithelial – like characteristics. The study of fibronectin expression in these cells suggests that FS cells may help regulate pituitary function, by interacting with hormone secreting cells through fibronectin. Furthermore, as FS cells express vimentin, an intermediate filament protein marker, this supports the theory that FS cells may be derived from glial neuroectodermic cells.

Due to the different array of markers expressed in these cells, it is difficult to specify their exact cell-type and function. Multiple FS cell lines have been developed to try to observe the location and function of these cells. Recently the mRNA levels of FS cells can now be observed via laser capture microdissection and RT-PCR, so progress is being made in terms of understanding the expression and function of these non-endocrine cells of the pituitary. As they have multiple markers, it is plausible that these cells are a hybrid of several different cell types.

Function as sustentacular cells
Folliculostellate (FS) cells are asserted to be of sustentacular (support) function due to their positioning along-side the endocrine (hormone-secreting) cells of the pituitary gland, implying an either mechanical or chemical support – by forming structural support around the endocrine cells or releasing growth factors and cytokines (cell-signalling molecules). Structural support is exemplified in that FS cells are known to produce Metalloprotease inhibitor which may protect the basement membrane and maintain three-dimensional structural support; as well as surrounding endocrine cells, forming close contact to provide the growth factors and cytokines, within the pituitary gland.

As well as growth factors and cytokines, FS cells produce nitrogen oxide (NO). FS cells are considered to produce NO in order to control NO production in nearby endocrine cells, by expressing nNOS (an enzyme involved in NO production).

The production of IL-6 (interleukin-6, a cytokine) could also be said to be a supportive function, as the IL-6 is a mediator in communication between the endocrine and immune system. This IL-6 production by FS cells induces hormone production from endocrine cells, which can then activate the immune system.

There has been some suggesting evidence through numerous studies that FS cells may act as pituitary stem cells (SC). More specifically, using the S100β marker to identify FS cells and isolate them scientists have manage to find a connection between these cells and the production of interconnections and gap junction  with nearby FS cells, as well as activation of proliferation. Nonetheless, these processes need to require the presence of a laminin receptor (integrin β1) in combination with FS cells otherwise FS are incapable of proliferating

Moreover, FS as well as what is remaining of the Rathke’s pouch (the structure which gives rise to the anterior pituitary) known as the marginal zone seem to be involved in a cell renewal system for hormonal cells. Indirect evidence from goat as well as rat cell’s has lead to suggestions that the s100β+ cells may act as intermediate cells during the formation of adult pituitary cells as well as their possible contribution to junctions between cells Nonetheless, more research needs to be done regarding the direct linkage between FS and their stem cell behavior.

Role as signalling mediators for pituitary endocrine cells: Nitric oxide and interferon gamma
FS Cells are thought to have a role in relaying signals to the hormone secreting endocrine cells of the pituitary gland. Nitric Oxide (NO), is reported to be a key modulator of endocrine cell function and has been shown that FS cells (and some endocrine cells) contain a key NO production enzyme, neuronal NO synthase which is responsible for the production of NO from L-arginine. It is thought that FS cells modulate NO production in adjacent endocrine cells via paracrine mechanisms.

Interferon-gamma is a cytokine that’s action is to inhibit the release of various hormones from the anterior pituitary, FS cells are thought to be vital in mediating this process. This facilitating role of FS cells was identified when studying the anterior pituitary glands of rats, as anterior pituitary samples with few FS cells failed to exhibit the usual inhibitory effects of interferon-gamma. The protein Annexin 1(ANXA1), found in high quantities in the anterior pituitary gland, is located specifically in the folliculostellate cell. In addition to the anterior pituitary gland, it can also be found in the non-endocrine cells of the hypothalamus. In both these anatomical sites – Annexin 1 acts to inhibit the release of ACTH and CRH, respectively. The protein is stimulated to do this by glucocorticoids and is consequently a mediator of glucocorticoid induced suppression of the Hypothalamic-Pituitary-Adrenal Axis (HPA axis).

Glucocorticoid induced suppression of the HPA axis has 2 components. Firstly, within 15 minutes of increased glucocorticoid exposure in the anterior pituitary, there is a reduction in the release of preformed ACTH. Secondly, glucocorticoids act at a genomic level by suppressing the translation of ACTH and CRH – this process takes 2 hours after exposure to increased glucocorticoid.

Glucocorticoids act on the folliculostellate cells to increase synthesis of ANXA1 and then stimulate its translocation to the cell surface of the FS cell. This translocation is dependent on protein kinase C. ANXA1 subsequently acts on the endocrine cells of the anterior pituitary, which express ANXA1 G protein coupled receptors, via a paracrine mechanism. The downstream signalling pathway which culminates in reduced ACTH synthesis and/or release remains largely unexplored and as consequence remains poorly understood.

The glucocorticoid/folliculostellate cell relationship also has a role in the production of the excitatory neurotransmitter glutamine. Cells in rat anterior pituitary gland which contain large quantities of the enzyme glutamine synthetase also express the S100 protein which is the marker for folliculostellate cells. After exogenous glucocorticoid administration, the number of these cells increases and the activity of glutamine synthetase also increases. This enzyme is necessary as it allows the CNS to produce glutamine internally. This is essential as the quantity of glutamine transported from the peripheral blood to the CNS cannot satisfy the demands of the CNS for glutamine.