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Folliculostellate cells


Folliculostellate (FS) cells are non-granulated non-hormonal cells lining follicular structures and making a network of cells with cytoplasmic extentions between the hormonal cells (reviewed in [1414] [1415] [1416] [1417]). They were discovered by Rinehart & Farquhar [1418] more than half a century ago and initially thought to be supportive cells, although for some time they were proposed as being the cells producing ACTH (corticotrophs). They were originally named follicular cells for their characteristic to join with each other to make an anastomosing channel system of small follicles throughout the gland. The name folliculostellate cell (FS cell) was introduced by Vila-Porcile [668], to indicate both their follicular and stellate appearances. FS cells are found in the adenohypophysis of all vertebrate classes [1435] [1436] [1437] [1438] [1439] [1440] [1441], including the sea lamprey, a modern representative of agnathans [1442].

Microanatomical architecture:

In the centre of the hormonal cell cord (lobule), FS cells can arrange in clusters and form follicles, usually of submicroscopic size in the rat but in other species, including human, of a larger size [668] [669]. In the follicles numerous micro-villi protrude and some cilia are present. Follicle-forming FS cells are polarised. At the apical pole, bordering the follicle, they form tight junctions among each other and, more laterally, junctions of the “zonula adhaerens” type (desmosomes) [668]. Junctions among FS cells, however, are not always fully sealed [670] and do not isolate compartments from diffusion of biological molecules; intercellular spaces (between hormonal cells) are also freely accessible for diffusing molecules [672] [673].The baso-lateral side makes contact with the hormonal cells and with other FS cells, and extends processes that end on the basal membrane surrounding the cell cords.

A second group of FS cells extends long cytoplasmic processes between the hormonal cell types within each glandular cell cord [668]. These processes also form intercellular junctions, mostly of the zonula adherens-type, among each other [671] (see also [672] [673]). Some FS cells make intimate foot processes with the basal membrane of the extra-vascular spaces at the periphery of the glandular cell cords [668] [669]. In some species, FS cells located in the periphery of the cell cords are juxtaposed in a way that they form sinusoid-like spaces [674]. Intercellular lacunae are also often seen between hormonal cells [668]. Apparently, lacunae between hormonal cells, sinusoid-like spaces surrounded by FS cells and peri-vascular spaces form a micro-channel system within the pituitary, through which hormones, paracrine factors, nutrients, ions and waste products can circulate. Such a channel system is thought to play an important physiological role, although the precise details and regulation of flow remain obscure.


In infant rats (10 days of life) the FS cell follicles are elongated and participating FS cells have a columnar shape without cellular extensions and displaying very little intercellular junctions. Later on (30 days) they separate into smaller follicular units and start making extensions and junctions, especially tight junctions [669]. It appears, therefore, that the micro-channel function is more related to the mature pituitary physiology than to the development of the gland. It should be noted that FS cells identified on morphological basis in infant rats do not express the typical marker S100 protein before postnatal day 10.


Characterisation of FS cell functions has been considerably improved since these cells can be identified on the basis of both cellular and functional molecules. Most if not all FS cells express the S100 protein (for review see [82]). Subpopulations of FS cells also express GFAP [1419] [1421] [1424], cytokeratins [1420] [1421],vimentin [1422] and fibronectin [1423]. The functional marker of FS cells is uptake of the fluorescent dipeptide ß-Ala-Lys-N -AMCA [663]. Several FS cell lines have been produced such as TtT/GF (mouse) [664], Tpit/F1 (mouse) [665], FS/D1h (rat) [95] and PDFS cells (human) [666]. Recently, transgenic mice have been generated that express green fluorescent protein driven by the S-100 gene promoter [667]. It is now also possible to study mRNA levels in FS cells by laser capture microdissection followed by RT-PCR [792].

Gap junctions

A striking characteristic of FS cells is that they make gap junctions [1443] [1448], mostly with adjacent FS cells [669] [1449] but also with a few hormonal cells [677]. Junctions among FS cells are incomplete and do not seal off compartments from diffusion of biological molecules; intercellular spaces (between hormonal cells) are also freely accessible for diffusing molecules [672] [673]. FS cells are excitable and electrotonically coupled through their gap junctions, as shown by rapid transduction of Ca2+ currents over long distances in the gland [678] and by electrophysiological recordings [1448]. On this basis they are thought to coordinate activity of hormonal cells. Consistent with a function of FS cells in coordination of glandular cells is the observation in the mink, that the expression of the gap junctional protein connexin-43 increases in parallel with increased activity of the PRL cells in the breeding season [681]. Also in the rat there is an obvious correlation between the number of gap junctions and reproductive maturation [669]. In immature pituitary, gap junctions are poorly developed, but there is a steep rise at puberty. During the estrus cycle their number is lowest at diestrus. There is an increase at the end of pregnancy and during lactation. GnRH and testosterone markedly increase the number of gap junctions.

FS cells of the 'transitional zone'

The transitional zone is located in the most rostral zone of the adenohypophysis between the pars tuberalis, the anterior lobe and the intermediate lobe [1443] [1444]. In the rat 50 % of the cells in that zone are FS cells [1443] [1444]. From there a dense FS cell population extends to the posterior end along the basal plane of the gland  [1444]. Portal vessels enter the anterior lobe through the transitional zone and show a parallel distribution as FS cells towards the posterior end [1444]. In the transitional zone the density of connexin43-positive gap junctions between FS cells is also very high [1443] [1448]. These FS cells appear to make a functional sincitium propagating signals from there over the gland [1449].

The transitional zone also contains neuronal elements consisting of myelinated fibers, unmyelinated fibers, neuroendocrine fibers, large cells, and supporting cells. FS cells intermingle with these neuronal elements [1445]. Some of the neuroendocrine fibers are GnRH neuronal fibers. GnRH  fibers end in the vicinity of the portal vessels but some fibers are not related to the vessels and make direct contact with FS cells in the transitional zone [1446] [1447]. Based on these microanatomical specializations it is thought that GnRH not only stimulates gonadotropin secretion via the portal blood but also modulates the activity of gonadotrophs by directly exciting FS cells that, in turn, can transmit the local signal in the transitional zone via the FS cell network onto the gonadotrophs throughout the gland  [1446] [1447] [1448]. Long-distance electrotonic coupling has indeed been demonstrated in the transitional zone  by electrophysiological recordings and since the coupling is blocked by carbenoxolone, coupling appears to occur via gap junctions [1448].

Micro-circulation of nutrients, ions and waste products.

In a series of elegant in vitro experiments, using a near-homogenous FS cell population from bovine anterior pituitary or pars tuberalis, Ferrara presented strong evidence that FS cells can make tight and functionally polarised epithelia, displaying the typical ion transport characteristics of such epithelia [675] [676]. Monolayers of these FS cells, grown on polycarbonate filters and placed in Ussing chambers, show a transepithelial potential difference of ~1.1 mV and a short-circuit current, consistent with transepithelial ion transport. These confluent cultures also made domes, a typical feature of cultures of transporting epithelia. The current is inhibited by ameloride applied at the mucosal surface and further depressed by ouabain applied at the serosal surface, indicating a current made by active Na+ absorption. Also the domes collapsed after treatment with ameloride [675]. Interestingly, the current is increased by β-adrenergic agonists, prostaglandin E2, bradykinin and lysine vasopressin [675] [676].


FS cells may have a role in phagocytosis. The cells may contain phagocytosed cell debris that show secretory granules containing hormone, such as PRL or GH, and such cells are more conspicuous when certain hormonal cells regress after a period of hyperplasia (reviewed in [82]).

Pituitary cell renewal

Several groups proposed, although without direct evidence, that the FS cells and the marginal zone cells, that have many characteristics in common with each other [668] [669], may form a cell renewal system for hormonal cells [668] [669] [1397] [1398] [1399] [1400]. The marginal zone surrounds the pituitary cleft and is the remnant zone of the embryonic Rathke’s pouch. During the early embryonic period, proliferation of pituitary progenitor cells occurs in the vicinity of the pouch lumen after which cells migrate and start to differentiate [791]. In analogy it was thought that the marginal zone cells surrounding the pituitary cleft during postnatal life may have a role as a germinative layer during postnatal expansion of the gland and various lines of indirect evidence support that view. In postnatal rats, mitotic activity in the marginal cell layer and in the typical follicular cells that surround pituitary follicles is considerably higher than in the parenchymal endocrine cells [1401] [1402]. Cells ultrastructurally similar to FS cells (but not expressing yet S100) in 10-day-old rats are junction-poor columnar cells making elongated follicles (intragladular extensions of the cleft?) that gradually convert into the normal adult cellular architecture around 40 days of life [669]. In the goat pituitary, numerous GH immunopositive cells) have been found to express S100, and also some PRL and TSH cells weakly express S-100, a finding that made the authors suggest that these cells may represent a possible intermediary cell en route for becoming fully differentiated hormonal cells [1403]. When the anterior pituitary is transplanted under the kidney capsule, there is necrosis of the glandular tissue except at the surface of the transplant where the marginal zone is located. The latter cells rapidly start to show mitotic figures, and cystlike structures appear that are lined by agranular cells and are connected to the cleft by narrow cavities. At 20 days after transplantation, granular cells lining the cavities appear, suggestive for transformation of marginal cells into hormonal cells [1404]. Transgenic targeting of LIF expression in GH cells results in conspicious development of Rathke’s cysts lined by ciliated cuboidal cells, focally immunopositive for cytokeratin and S-100 [1407]. Finally, the pituitary-specific transcription factor Ptx1, that is expressed in all hormonal cell types, is also detectable in a subpopulation of FS cells and in the TtT/GF FS cell line, consistent with a common origin for hormonal and S100 cells in the postnatal pituitary [1405]. Interestingly, most cells of the marginal layer of the intermediate lobe of the rat are immunoreactive for either S-100 or serotonin [1406], opening interesting avenues for exploring a putative role of local serotonin in the development or functioning of the presumed candidate stem cells, particularly in view of the fact that serotonin is a powerful regulator of adult neurogenesis in the hippocampus and that the 5-HTR3 is temporarily highly expressed in Ratke’s pouch during embryonic life [1409].

Paracrine functions

Many paracrine functions have been proposed for FS cells. See "FS cell actions"


Expression of the proteoglycan syndecan-4 and the mechanism by which it mediates stress fiber formation in folliculostellate cells in rat anterior pituitary gland. Horiguchi K, Kouki T, Fujiwara K, Tsukada T, Ly F, Kikuchi M, Yashiro T. J Endocrinol. 2012 May 29. [Epub ahead of print] PMID: 22645300

Living-cell imaging of transgenic (S100b-GFP) rat anterior pituitary cells in primary culture reveals novel characteristics of folliculo-stellate cells. Horiguchi K, Kikuchi M, Kusumoto K, Fujiwara K, Kouki T, Kawanishi K, Yashiro T. J Endocrinol. 2009 Nov 9. [Epub ahead of print]

The changes of gap junctions between pituitary folliculo-stellate cells during the postnatal development of Zucker fatty and lean rats. Sakuma E, Wada I, Soji T, Wakabayashi K, Otsuka T, Herbert DC. Microsc Res Tech. 2014 Jan;77(1):31-6. PMID: 24738148

Intercellular communications within the rat anterior pituitary. XVI: postnatal changes of distribution of S-100 protein positive cells, connexin 43 and LH-RH positive sites in the pars tuberalis of the rat pituitary gland. An immunohistochemical and electron microscopic study. Wada I, Sakuma E, Shirasawa N, Wakabayashi K, Otsuka T, Hattori K, Yashiro T, Herbert DC, Soji T. Tissue Cell. 2014 Feb;46(1):33-9. doi: 10.1016/j.tice.2013.10.001. Epub 2013 Oct 9. PMID: 24216131

Expression of Slug in S100β-protein-positive cells of postnatal developing rat anterior pituitary gland. Horiguchi K, Fujiwara K, Tsukada T, Yako H, Tateno K, Hasegawa R, Takigami S, Ohsako S, Yashiro T, Kato T, Kato Y. Cell Tissue Res. 2015 Aug 7. [Epub ahead of print] PMID: 26246400

Ultrastructural changes in lactotrophs and folliculo-stellate cells in the ovine pituitary during the annual reproductive cycle. Christian HC, Imirtziadis L, Tortonese D. J Neuroendocrinol. 2015 Feb 4. doi: 10.1111/jne.12261. [Epub ahead of print] PMID: 25650820

Anterior pituitary cell networks. Le Tissier PR, Hodson DJ, Lafont C, Fontanaud P, Schaeffer M, Mollard P. Front Neuroendocrinol. 2012 Aug;33(3):252-66. doi: 10.1016/j.yfrne.2012.08.002. Epub 2012 Sep 7. Review. PMID: 22981652

Anterior and intermediate pituitary tissues express claudin 4 in follicle stellate cells and claudins 2 and 5 in endothelial cells. García-Godínez A, Contreras RG, González-Del-Pliego M, Aguirre-Benítez E, Acuña-Macías I, de la Vega MT, Martín-Tapia D, Solano-Agama C, Mendoza-Garrido ME. Cell Tissue Res. 2014 Apr 24. [Epub ahead of print] PMID: 24760107

Folliculo-stellate cells - potential mediators of the inflammaging-induced hyperactivity of the hypothalamic-pituitary-adrenal axis in healthy elderly individuals. Jovanović I, Ugrenović S, Ljubomirović M, Vasović L, Cukuranović R, Stefanović V. Med Hypotheses. 2014 Oct;83(4):501-5. doi: 10.1016/j.mehy.2014.08.018. Epub 2014 Aug 23. PMID: 25175404

Proton receptor GPR68 expression in dendritic-cell-like S100β-positive cells of rat anterior pituitary gland: GPR68 induces interleukin-6 gene expression in extracellular acidification. Horiguchi K, Higuchi M, Yoshida S, Nakakura T, Tateno K, Hasegawa R, Takigami S, Ohsako S, Kato T, Kato Y. Cell Tissue Res. 2014 Aug 17. [Epub ahead of print] PMID: 25129106

Immunohistochemical localization of anterior pituitary hormones in S-100 protein-positive cells in the rat pituitary gland. Kikuchi M, Yatabe M, Tando Y, Yashiro T. Cell Tissue Res. 2011 Sep;345(3):425-9. doi: 10.1007/s00441-011-1214-6. Epub 2011 Aug 10. PMID: 21830043

Characterization of adherens junction protein expression and localization in pituitary cell networks. Chauvet N, El-Yandouzi T, Mathieu MN, Schlernitzauer A, Galibert E, Lafont C, Le Tissier P, Robinson IC, Mollard P, Coutry N. J Endocrinol. 2009 Sep;202(3):375-87. doi: 10.1677/JOE-09-0153. Epub 2009 Jun 8.

Estrogen receptor alpha regulates retinaldehyde dehydrogenase 1 expression in rat anterior pituitary cells. Fujiwara K, Kikuchi M, Horiguchi K, Kusumoto K, Kouki T, Kawanishi K, Yashiro T. Endocr J. 2009;56(8):963-73. Epub 2009 Aug 11.

Chicken folliculo-stellate cells express thyrotropin receptor mRNA. Grommen SV, Geysens S, Darras VM, De Groef B. Domest Anim Endocrinol. 2009 Nov;37(4):236-42. doi: 10.1016/j.domaniend.2009.06.003. Epub 2009 Aug 8

Living-cell imaging of transgenic rat anterior pituitary cells in primary culture reveals novel characteristics of folliculo-stellate cells. Horiguchi K, Kikuchi M, Kusumoto K, Fujiwara K, Kouki T, Kawanishi K, Yashiro T. J Endocrinol. 2010 Feb;204(2):115-23. doi: 10.1677/JOE-09-0333. Epub 2009 Nov 9.

Immunohistochemical localization of aquaporin-4 in the rat pituitary gland. Kuwahara S, Maeda S, Ardiles Y, Jun JG, Tanaka K, Hayakawa T, Seki M. J Vet Med Sci. 2010 Oct;72(10):1307-12. Epub 2010 May 18.

Systemic administration of lipopolysaccharide increases the expression of aquaporin-4 in the rat anterior pituitary gland. Kuwahara-Otani S, Maeda S, Tanaka K, Hayakawa T, Seki M. J Vet Med Sci. 2013;75(8):1081-4. Epub 2013 Mar 22.

Immunohistochemical Localization of the Water Channels AQP4 and AQP5 in the Rat Pituitary Gland. Matsuzaki T, Inahata Y, Sawai N, Yang CY, Kobayashi M, Takata K, Ozawa H. Acta Histochem Cytochem. 2011 Dec 28;44(6):259-66. doi: 10.1267/ahc.11031. Epub 2011 Oct 22.

The extracellular matrix component laminin promotes gap junction formation in the rat anterior pituitary gland. Horiguchi K, Kouki T, Fujiwara K, Kikuchi M, Yashiro T. J Endocrinol. 2011 Mar;208(3):225-32. doi: 10.1677/JOE-10-0297. Epub 2010 Dec 22.

Loss of the NHE2 Na+/H+ exchanger in mice results in dilation of folliculo-stellate cell canaliculi. Miller ML, Andringa A, Schultheis PJ, Shull GE. J Biomed Biotechnol. 2011;2011:510827. doi: 10.1155/2011/510827. Epub 2011 Jan 10.

Involvement of the adrenal glands and testis in gap junction formation via testosterone within the male rat anterior pituitary gland. Sakuma E, Wada I, Otsuka T, Wakabayashi K, Ito K, Soji T, Herbert DC. Microsc Res Tech. 2012 Dec;75(12):1632-8. doi: 10.1002/jemt.22108. Epub 2012 Jul 31.

Characterization of a pituitary-tumor-derived cell line, TtT/GF, that expresses Hoechst efflux ABC transporter subfamily G2 and stem cell antigen 1. Mitsuishi H, Kato T, Chen M, Cai LY, Yako H, Higuchi M, Yoshida S, Kanno N, Ueharu H, Kato Y. Cell Tissue Res. 2013 Nov;354(2):563-72. doi: 10.1007/s00441-013-1686-7. Epub 2013 Jul 24.

Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. 1989. Ferrara N, Henzel WJ. Biochem Biophys Res Commun. 2012 Aug 31;425(3):540-7. doi: 10.1016/j.bbrc.2012.08.021. No abstract available. PMID: 22925671

Differentiation capacity of native pituitary folliculo-stellate cells and brain astrocytes. Osuna M, Sonobe Y, Itakura E, Devnath S, Kato T, Kato Y, Inoue K. J Endocrinol. 2012 Mar 20. [Epub ahead of print] PMID: 22434586

Evidence from in vitro and in vivo studies that NFκB within the pituitary folliculostellate cells and corticotrophs regulates ACTH secretion in experimental endotoxaemia. Mehet DK, Philip J, Solito E, Buckingham JC, John CD. J Neuroendocrinol. 2012 Jan 27. doi: 10.1111/j.1365-2826.2012.02285.x. [Epub ahead of print] PMID: 22283629

Matrix metalloproteinase-9 expression in folliculostellate cells of rat anterior pituitary gland. Ilmiawati C, Horiguchi K, Fujiwara K, Yashiro T. J Endocrinol. 2011 Dec 19. [Epub ahead of print] PMID: 22182603