Folliculostellate (FS) Cells

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Starting a separate thread on these cells which I mentioned in the buspirone/prolactin thread here. This may just be something I’m interested in for new shiny novelty reasons but I haven’t found any discussion on the forum and they seem really interesting and also potentially relevant to various theories.

How some specialists have banged on about the HPA axis for years and yet not shown any interest in cells that seem to have significant involvement in pituitary responses and links to the immune system. But I digress…

I’ll post some links to things to read, papers and my notes/summaries and maybe others will be interested and dig around a bit and pose some questions too.

 

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Wikipedia is a good place to start as is often the case
Folliculostellate cell
And there’s an abstract here: Folliculostellate cells: what are they?

Rinehart and Farquhar first discovered FS cells through electron microscopy of the anterior pituitary gland. Vila-Porcile named these non-endocrine cells "folliculo-stellate" cells in 1972 due to their stellate (star) shape, and their location lining the lumen of small follicules in the anterior pituitary

Pituitary folliculostellate (FS) cells were originally described in 1953 and comprise up to 10% of the anterior pituitary cell population

Experiments using pituitary slices have demonstrated that FS cells are organised structurally into three-dimensional networks capable of intercellular communication via gap junction-mediated calcium wave propagation

Studies using these cell lines have demonstrated a role for FS cells in three broad areas of pituitary function: autocrine/paracrine regulation of anterior pituitary cell function via cytokines and growth factors, intrapituitary communication between various cell types, and modulation of inflammatory responses.

The concept of FS cells as key mediators in the neuro-immune/endocrine regulation of inflammation is gaining credence and is supported by evidence on several levels including expression of components of the innate immune system (C3a, C5a receptors), secretion of inflammatory cytokines (IL-6 and MIF) and regulation of these cytokines by anti-inflammatory molecules (including glucocorticoids and adenosine)

recent observations suggest that pituitary FS cells are not a homogeneous population but comprise subsets of cells with different immunophenotypes, though it is unclear whether these populations are truly distinct or merely represent cells at differing stages of development.

 

[V.R.T.]

The concept of FS cells as key mediators in the neuro-immune/endocrine regulation of inflammation is gaining credence and is supported by evidence on several levels including expression of components of the innate immune system (C3a, C5a receptors), secretion of inflammatory cytokines (IL-6 and MIF) and regulation of these cytokines by anti-inflammatory molecules (including glucocorticoids and adenosine)

This looks like it could be very relevant. Of course a lot of things do but it's interesting still.

Good find. How would we determine if these cells are involved in ME/CFS?

 

[V.R.T.]

There’s also a big old review here which touches o some interesting ideas of how these cells manage the pitutary axes and may deal with memory or anticipation of demand.

(This may be one for another thread of ‘things hotblack has found interesting’ rather than clogging up discussion here, I can move in the morning if needed)
Edit: thread for all things Folliculostellate cell

Renewing an old interest: Pituitary folliculostellate cells, 2021, Le Tissier et al

Le Tissier, Paul R.; Mollard, Patrice

Abstract
Anterior pituitary folliculostellate (FS) cells, first described almost 50 years ago, have a wide range of functions with respect to supporting and coordinating endocrine cell function, in particular through paracrine and gap junction‐mediated signalling.

Our previous studies identified the morphological organisation of FS cells, which mediates coordinated calcium activity throughout the homotypic FS network and allows signalling across the whole pituitary gland. It is also clear that FS cells can modify endocrine output and feedback on pituitary axes over a range of timescales.

Recently, several studies have defined FS cells as a source of anterior pituitary endocrine cell renewal, which has resulted in a renaming of FS cells as “Sox2+ve stem cells”.

Here, we highlight the broader potential of the FS cell population in fine‐tuning and coordinating pituitary axes function. In addition, we identify a need for: the definition of the possible subtypes of FS cell and their relationship with the stem cell population; the potential role of FS cells in pulsatile hormone secretion and coordination of heterotypic cell networks; and the roles that FS cells may play in both early‐life programming of pituitary axes and in memory, or anticipation, of demand.

Further studies of FS cells may demonstrate the fundamental importance of this cell type and its potential as a therapeutic target to correct pituitary gland dysfunction, one of which is stem cell therapy. Clearly, a thorough understanding of all of these interactions and relationships of FS and endocrine cells is required whatever therapeutic use is suggested by their various roles.

Web | DOI | PMC | PDF | Journal of Neuroendocrinology

Also this post from the buspirone thread caught my interest. A link with cognition is really intriguing. The anticipation of demand thing made me think about how sometimes I start to crash just thinking through the logistics of something I have to do.

 

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I have loads more half made notes and papers to go through. I don’t want to paste things which may mislead. Bear with me and hopefully I’ll be able to get to more in time. And hopefully others will be able to help answer the questions which arise. I’d never heard of these things until this week so am far from an authority!

 

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Good find. How would we determine if these cells are involved in ME/CFS?

That’s a really good question! I’d be interested in hearing what others think. Given discussion in the prolactin thread I wonder if there’s any PET tracers which could be used to measure relevant signalling molecules or just measuring blood levels (they may be masked and not give us cell specificity though). But maybe there’s other more appropriate approaches.

 

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Rather than posting full papers and abstracts I’ll include their details and some selected passages that I find interesting and maybe some of my notes. So a bit curated and interpreted, but hopefully not too far off the mark!

The more modern review @V.R.T. linked to is a good place to start along with a couple of older ones

An Insight to Pituitary Folliculo‐Stellate Cells, 2008, Devnath et al
Devnath, S.; Inoue, K.
Web | DOI | Journal of Neuroendocrinology

These FS-cells have a characteristic star-like morphology accounting for 5–10% of all pituitary cells and form follicles. Usually, FS-cells are found lining the lumen of tiny- or pseudo-follicles that are scattered throughout the anterior pituitary gland. Their long slender cytoplasmic processes intermingle in a fashion that produces a three-dimensional (3D) anatomical network, in the meshes of which hormone-secreting cells reside.

Many features of FS-cells remained unknown until S-100b protein was reported as a marker protein. Because FS-cells are non-endocrine cells, immunohistochemical detection using an antibody against a hormone cannot be used. This fact hampered the study of FS-cells and delayed their investigation compared with hormone-producing pituitary cells.

Thus, a number of studies were carried out on FS-cells after the identification of the S-100b marker protein. Indeed, S-100b protein has been a powerful tool that allows the visualisation of FS-cells under the light microscope.

The development of the FS-cell line also holds much promise for exploring FS-cells. Glial fibrillary acidic protein (GFAP) is another cytochemical marker for FS-cells and the establishment of GFAP-positive cell line (TtT ⁄ GF), a suitable model for FS-cells, has facilitated research on FS-cells. We have also developed another cell line, namely Tpit ⁄ F1, which has FS-cell-like characteristics with neuronal NO synthase (nNOS).

In addition, we recently developed a transgenic rat expressing green fluorescent protein (GFP) under a cell-specific promoter of the S-100b protein gene. The transgenic rats produce GFP specifically in FS-cells, which may provide a new approach for studying FS-cells in the future.

The phagocytotic activity of FS-cells has been clearly demonstrated in the pituitary glands of oestrogen- deficient and dopamine-treated rats, which is known to induce apoptosis of prolactin cells. Further proof of scavenging activity of FS-cells came to light after studying colloid formed in the pituitary gland.

Colloids are surrounded by FS-cells and it is generally accepted that the major part of colloids is produced by FS-cells. An extensive analysis of colloids suggests that colloidal materials arise as a by-product of cellular degradation, and that clusterin is major protein component therein. However, clusterin is not locally synthesised in FS-cells, rather it is produced in endocrine cells.

FS-cells are also suspected to have some sort of ammonia scavenging function. A high concentration of glutamic acid ⁄ glutamine has been detected in FS-cells.

Shirasawa and Yamanouchi revealed the existence of glucocorticoid-inducible GS enzyme in FS-cells in the rat. FS-cells are therefore suspected to control glutamate levels and to scavenge toxic ammonia to sustain glutamine stocks.

 

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My summary would be that the FS cells act as scaffolding and a mesh around the hormone producing cells, they were thought to do nothing more and not easy to study until it was found they express the marker protein S100B. Interestingly this is a glial protein primarily expressed by astrocytes, so there’s a biological similarity here. Further studies found another glial/CNS marker protein on FS cells in GFAP.

With new tools and use of those fun ‘glow in the dark’ rat models more studies have been possible on these cells. These have shown the cells seem to act as clean up crew in a similar way to astrocytes. Absorbing old hormone producing cells as they die and sequestering clusterin, glutamate and ammonia. This is often stored away from either hormone producing or FS cells in little pockets or colloids.

 

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Next paper, the one @V.R.T. mentioned and I’ll start with those bits from the abstract as they’re intriguing, but then dive into the rest of the paper

Renewing an old interest: Pituitary folliculostellate cells, 2021, Le Tissier et al
Le Tissier, Paul R.; Mollard, Patrice
Web | DOI | PMC | PDF | Journal of Neuroendocrinology

Our previous studies identified the morphological organisation of FS cells, which mediates coordinated calcium activity throughout the homotypic FS network and allows signalling across the whole pituitary gland.

It is also clear that FS cells can modify endocrine output and feedback on pituitary axes over a range of timescales. Recently, several studies have defined FS cells as a source of anterior pituitary endocrine cell renewal, which has resulted in a renaming of FS cells as “Sox2+ve stem cells”.

Here, we highlight the broader potential of the FS cell population in fine‐tuning and coordinating pituitary axes function.

In addition, we identify a need for: the definition of the possible subtypes of FS cell and their relationship with the stem cell population; the potential role of FS cells in pulsatile hormone secretion and coordination of heterotypic cell networks; and the roles that FS cells may play in both early‐life programming of pituitary axes and in memory, or anticipation, of demand.

 

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Some more details, there’s a lot in this review! I may need to come back and split it up a bit (sorry for the wall of text but if I don’t post it I’ll lose the text or my mind) but some highlights

Edit: Still a lot of text but hopefully easier now it’s in sections.

Structure and extra cellular matrix

Early studies of the morphological organisation of FS cells described them as star‐shaped cell, with cell bodies located among secretory cells and with processes extending between secretory cells and terminating at the perivascular space of capillaries

A role for the chemoattractant molecule CXCL12 and its receptor CXCR4, both expressed by FS cells, has been described in this in vitro recapitulation of cell organisation

An important interaction of FS cells with the extracellular matrix (ECM) has also been described, with matrix metalloprotease 9 mediating cell organisation, integrin ß1 signalling regulating FS cell proliferation and FS cell production of tissue inhibitors of metalloproteinases in turn regulating the ECM

Cell networks and calcium waves

The extensive FS organisation across the pituitary gland recognised by Vila‐Porcile, as well as the relationship with other pituitary hormonal cell types, led to a recognition that FS cells may mediate pituitary scale regulation and the coordination of endocrine output.

Furthermore, because the AMCA dye can be imaged in live cells, we were able to record calcium activity in FS cells, revealing spontaneous changes in cytosolic calcium, with a large proportion of cells firing monophasic calcium spikes. Communication across the gland is apparent as a wave of calcium activity that travels through the FS cell network from one wing of the pituitary to the other. Moreover, more localised cell–cell communication was evident within subsets of FS cells, suggesting specialised communication modes with endocrine cell neighbours

This calcium wave propagation is mediated by gap junctions between FS cells, which may also allow other small molecules (such as cAMP, inositol trisphosphate) to act as signals that can be transferred through the network.The role of this communication for FS cell function is currently unclear; however, pituitary cell organisation has been shown to have coordinating roles in a range of cell activities, including secretion and the regulation of gene expression.

Regulation of anterior pituitary output - prolactin and cytokines

FS cells have been shown to produce a range of growth factors and cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, annexin 1 (ANXA1) and interleukin‐6, as well as nitric oxide (NO), all of which have clear roles in the regulation of specific endocrine pituitary cell types

whereas FS cell (intriguingly those near blood vessels) NO synthase expression has been shown to be increased by dopamine, potentially mediating some of the inhibitory actions of this small transmitter on prolactin release

Relayer of peripheral feedback signals?

Perhaps the most intriguing potential roles for FS cells, in terms of potential coordinators of endocrine function as well as stem cells, is their response to pituitary target organ feedback and mediators

For example, in the prolactin axis, FS cells have been shown to mediate lactotroph proliferation in response to estradiol, an effect that is blocked by progesterone

These effects are most likely primarily through paracrine interactions, especially because interleukin‐6 has a regulatory role on lactotrophs

Glucocorticoids and corticotrophs

Of the paracrine FS cell actions, perhaps the best characterised example is the modification of corticotroph function in response to glucocorticoid feedback through ANXA1

Glucocorticoids increase FS cell ANXA1 expression resulting in translocation of the protein to the external surface of the plasma membrane. The externalised ANXA then binds to high affinity binding sites on corticotrophs, resulting in a reduction of adrenocorticotrophic hormone (ACTH) secretion in response to corticotrophin‐releasing hormone

 

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A coordinator or the various pituitary axes and pulse generation

If we combine the biology described above with their more recent description as pituitary stem cells, it is clear that FS cells have a central role in anterior pituitary biology and that these different facets of their activity should not be considered in isolation. As a non‐hormonal cell type that allows communication across the entire gland and has modifying functions on all endocrine cell types, FS cells are ideally placed to coordinate the various pituitary axes.

Perifusion studies of isolated pituitaries have shown that hormone output is spontaneously pulsatile in the absence of hypothalamic input

Indeed, the paracrine and gap junction‐mediated communication between FS and endocrine cells would provide a mechanism allowing the coordination of pulsatile release over different timescales.

Indeed, modelling of the hypothalamic pituitary gonadal axis has suggested that altered FS cell function driven by oestradiol could have a role with respect to luteinising hormone surge driving ovulation.

For the hypothalamic pituitary adrenal and thyroid axes, there is strong evidence that pituitary pulsatile release is possible with an invariant hypothalamic secretagogue, and FS cells may have a primary role in pulse generation.

In the case of corticotroph output, modelling by Walker et al. has suggested that pulsatile ACTH can be driven by the delayed feedback of glucocorticoid, which would be consistent with the actions of glucocorticoid feedback on FS cell ANXA1.

Plasticity, remodelling over time and memory

Functional plasticity is an important feature of pituitary gland biology because the appropriate output of each pituitary hormone does not simply maintain homeostasis but is required to change dramatically in response to, as well as in anticipation of, physiological status

Modification of the number, size and morphological relationship of FS and endocrine cells in different physiological states, as well as with age, has been described, suggesting an altered function, although it is possible that FS cells play a more fundamental role

Obviously, stem cell function allows FS cells to alter the number of endocrine cells and this is likely an important feature in the expansion of specific cell types in response to challenge, such as the expansion of the lactotroph population in pregnancy and lactation in humans or the thyrotroph population in response to hypothyroidism

although ECM‐remodelling and maintenance roles for FS cells may also have important implications for endocrine cell network organisation, signalling and hormone output. Altered gap junction‐mediated signalling does not require a morphological rearrangement or change in cell number and we have observed changes in gap junction distribution in the lactotrophs of lactating dams

The memory of previous physiological status is another key aspect of anterior pituitary gland biology. Excellent examples of this are the programming of the hypothalamic pituitary adrenal axis by prenatal and perinatal stress and memory in the prolactin axis of lactational demand

Changes over time

Finally, we would suggest that, in addition to roles in maintenance of homeostasis, plasticity and memory, FS cells are uniquely placed to fine‐tune functional output and coordinate the function of pituitary axes. Key to this may be the FS cell response and modification of target organ feedback through altered paracrine and gap junction‐mediated signalling, as well as modification of feedback signals such as glucocorticoids or thyroid hormone.

In addition, the role of stem cells allows adjustment of the proportion of the different pituitary cell types, which may allow prioritisation of various axes with age; for example, increased growth hormone output at puberty which then declines with age.

Two additional features of FS cell biology may be permissive to this fine‐tuning: the lack of expression of several receptors for hypothalamic secretagogues and the ability to signal throughout the pituitary independent of blood flow.

 

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That’s it for the big posts. But hopefully a good overview of what these cells are! Those two papers were substantial reviews of many papers themselves so reducing their content wasn’t easy. It was at least useful for me in learning about them so I hope it may be for others.

 

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That’s it for the big posts. But hopefully a good overview of what these cells are! Those two papers were substantial reviews of many papers themselves so reducing their content wasn’t easy. It was at least useful for me in learning about them so I hope it may be for others.

Overall it seems that far from the original idea of being structural or scaffolding, FS cells are key to understanding behaviour of the pituitary. They form a complex network which communicates both within itself and with hormone producing cells. This communication happens via calcium signals but also various others including hormonal and immune. Changes can take place over different timescales, in response to different events and at different stages of life.