Pituitary (2013) 16:413–418 DOI 10.1007/s11102-013-0470-8
Pituitary stem cells: candidates and implications Farshad Nassiri • Michael Cusimano • Jeff A. Zuccato Safraz Mohammed • Fabio Rotondo • Eva Horvath • Luis V. Syro • Kalman Kovacs • Ricardo V. Lloyd
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Published online: 20 February 2013 Ó Springer Science+Business Media New York 2013
Abstract The pituitary is the master endocrine gland of the body. It undergoes many changes after birth, and these changes may be mediated by the differentiation of pituitary stem cells. Stem cells in any tissue source must display (1) pluripotent capacity, (2) capacity for indefinite selfrenewal, and (3) a lack of specialization. Unlike neural stem cells identified in the hippocampus and subventricular zone, pituitary stem cells are not associated with one specific cell type. There are many major candidates that are thought to be potential pituitary stem cell sources. This article reviews the evidence for each of the major cell types and discuss the implications of identifying a definitive pituitary stem cell type. Keywords Adenoma Adenohypophysis Marker Pituitary Stem cell Tumour
The pituitary is an endocrine gland that rests within the sella turcica at the base of the brain. It is considered the master
F. Nassiri (&) M. Cusimano J. A. Zuccato S. Mohammed Division of Neurosurgery, Department of Surgery, University of Toronto, 30 Bond Street, Toronto, ON M5B 1W8, Canada e-mail:
[email protected] F. Rotondo E. Horvath K. Kovacs Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, Canada L. V. Syro Department of Neurosurgery, Clinical Medellin and Hospital Pablo Tobon Uribe, Medellin, Colombia R. V. Lloyd Department of Pathology and Laboratory Medicine, University of Wisconsin Hospital and Clinics, Madison, WI, USA
endocrine gland of the human body. It consists of two components, the anterior pituitary (adenohypophysis) and posterior pituitary (neurohypophysis), which regulate numerous physiological processes such as metabolism, reproduction, growth, and response to stress via the secretion of its hormones. The adenohypophysis is composed of five different hormone-secreting cells: somatotrophs which secrete growth hormone (GH), lactotrophs which secrete prolactin (PRL), corticotrophs which secrete adrenocorticotropic hormone (ACTH), thyrotrophs which secrete thyroid stimulating hormone (TSH), and gonadotrophs whichs ecrete luteinizing hormone and follicle stimulating hormone (LH/FSH). The postnatal pituitary has a full set of terminally differentiated hormone producing cells [1]; however, it undergoes stages of growth that results in an increased glad size [2]. Moreover, the pituitary is able to change its cellular composition in response to different physiological conditions, such as growth, pregnancy, and lactation. Furthermore, the pituitary is able to regenerate after tissue injury [3]. The mechanism of regeneration and cellular adaptation is unknown, but is thought to be mediated either through the differentiation of stem cells, transdifferentiation of differentiated phenotypes, or mitoses of differentiated cells [4, 5]. The dogma that the adult brain was a static and quiescent organ was disputed by the discovery of neural stem cells that line the subventricular zone of the adult brain [6, 7]. In fact, there is now evidence that supports the regeneration of brain tissue via these stem cells [8]. Similarly, it is possible that plasticity and regeneration within the pituitary may be secondary to the activation of adult pituitary stem cells. The three fundamental characteristics of stem cells include: (1) pluripotency, (2) a lack of specialization, and (3) an indefinite self-renewal potential [9]. Moreover, cultured stem cells characteristically form spheres of pluripotent and undifferentiated cells that contain unique stem cell markers.
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Populations of pituitary cells that contain stem cell markers have previously been identified [10, 11]. Moreover, the minimal mitotic activity in pituitary tumors and the existence of null-cell type and plurihormonal adenomas suggest that pituitary stem cells may be a source of pituitary tumorigenesis [12]. In contrast to the studies on neural stem cells, which have clearly delineated astrocytes within the subventricular zone and hippocampus as the definitive neural stem cells, there is no consensus on which cells types can be considered as definitive pituitary stem cells. Chromophobes were the first groups of cells to be considered as potential pituitary stem cells [5]. Chromophobes are a heterogenous group of cells within the adenohypophysis that include, mesenchymal cells, degranulated hormonal cells, and agranular cells including folliculostellate, and marginal zone cells. The first evidence of chromophobes as potential pituitary stem cells candidates was published in 1969. In this study, purified chromophobes from excised pituitaries were transplanted into the hypophysiotrophic area of the rat hypothalamus. The transplanted chromophobes proliferated and differentiated into bothacidophil and basophil cells [5]. Moreover, chromophobes were also found to differentiate into mature acidophils and basophils in vitro [13]. However, studies on chromophobes were unable to demonstrate that these cells had the fundamental pluripotent characteristic of stem cells or that the regenerated tissue was endocrinologically active. Nevertheless, the individual chromophobic cell types are still considered to be major candidates for pituitary stem cells. More recently, a ‘‘side population’’ of cells, and a variety of other cells, have also been implicated as a potential source of pituitary stem cells. In this review we outline and discuss the evidence for the major pituitary stem cell candidates. We will also consider the implications for pituitary stem cells in the treatment of adenomas.
Folliculostellate cells Folliculostellate cells (FSCs) are stellate shaped epithelial follicular cells with long extensions that spread and interdigitate between hormone secreting cells of the adenohypohysis [14–16]. In humans FSCs line the lumen of large follicles throughout the adenohypophysis whereas in rats FSCs are generated in the early post-natal period and found adjacent to the pituitary cleft [17–19]. FSCs have small nuclei, numerous cytoplasmic polyribosomes, scant rough endoplasmic reticulum and small Golgi apparatuses. The FSCs are also immunopositive for S100 and for GFAP, although these immunoreactivities are only temporary in accordance with the FSC cell cycle [20–24]. The formation of follicles within the pituitary has been noted as early as 6 weeks of gestation, and by 8–10 weeks
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of gestation the morphology of these follicular cells is almost identical to those seen in the adult pituitary [25]. The main difference between the fetal and postnatal pituitary is the acinar architecture of the postnatal pituitary. It has been shown that FSCs are formed by glandular cells that surround foci of cell necroses thereby isolating the necrotic debris [26]. This formation occurs in three phases. First junctional complexes form between granulated cells. Next, the cells undergo degranulation and dedifferentiation of their cytoplasmic contents. Lastly, the cells are devoid of granulates and ultrastructual similarities to granulated cells [26]. In the latter stages the cells dismantle their endocrine machinery and assume the nonendocrine phenotype of the FSCs. Numerous studies have been able to demonstrate that FSCs may be a potential source of pituitary stem cells [9, 27, 28]. For example, it has been shown that the number of follicular cell clusters increases after gonadectomy, secondary to the loss of negative feedback [29]. Moreover, rodent pituitary grafts that were transplanted beneath the kidney capsule regularly differentiated into striated muscle cells that were in close association with folliculo-stellate cells [30]. Similarly, following transplantation into the kidney capsule, follicular cells both proliferate and granulate, and transform into immature acidophil and basophil cells [31]. These results have also been confirmed in vitro. Cultured Tpit/F1 cells, derived from pituitary stem cells and biochemically similar to FSCs with the expression of S100 and Ptx-1, were found to differentiate into myoglobin-positive multinuclear tubular cells. These cells were also positive for myogenin, a specific transcription factor for skeletal muscle cells [32, 33]. More recently, FSCs in adenomatous and nontumorous human pituitary glands were investigated [34]. The study showed that endocrine cells of both tumorous and nontumorous cell types were capable of transforming into FSCs while changing from an endocrine to non-endocrine phenotype. Stem/progenitor cells have the capability of forming colonies in vitro [35]. Colony-forming assays in adult mice have been used to characterize a population of putative stem/ progenitor cells located within the subluminal zone and marginal zone of the pituitary cleft [36–38]. Of all anterior pituitary cells, 0.2 % form colonies in vitro. These pituitary colony-forming cells (PCFCs) are hypothesized to be a subpopulation of pituitary folliculostellate (FS) cells based on their expression of S100-B and GFAP, as well as their ability to take up fluorescent didpeptide beta-Ala-Lys-N epsilon-AMCA (AMCA-positive) [36, 39]. A small proportion of these AMCA-positive FSCs have the capacity to form colonies: 12.3 % in vitro and one-third in vivo [36, 38]. PCFCs are agranular, highly proliferate, and are capable of dividing in [37, 38]. Interestingly, a small fraction (3.3 %) of
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AMCA-positive/GH-negative cells grown in vivo differentiated into GH-positive somatotrophs within 6 weeks [38]. Both somatotrophs and lactotrophs were seen at low levels in vitro [36]. This subset of anterior pituitary FS cells expands as an adherent colony and differentiates into multiple cell types. However, without evidence of self-renewal and differentiation into all five pituitary cell lineages, we cannot conclude that PCFCs are true stem cells. PCFCs likely represent committed progenitor cells with short-term proliferative capabilities rather than pituitary stem cells. This assertion is substantiated by the expression of progenitor cell associated markers (ACE and stem cell antigen-1) in many PCFCs [37]. As previously mentioned, stem cell markers are frequently used in stem cell studies. Nestin is an intermediate filament protein that has been implicated in stem cells in various tissues [40–42]. Nestin-positive cells have been identified in the pituitary [43]. These nestin positive cells were morphology similar to FSCs, and small subsets of these cells were also S100 positive. The nestin positive cells did not alter their morphological or proliferative activity after 10 passages suggesting the possibility of indefinite self-renewal capacity. However, despite this, none of the nestin positive cells differentiated into hormone secreting cells [43]. Few human pituitary studies demonstrating the stem cell potential of FSCs exist. Two human sellar neoplasms with simple cytoplasmic organization have previously been studied [44]. Ultrastructural analysis showed that both neoplasms contained a network of typical pituitary follicles and both neoplasms displayed a striking similarity to fetal human pituitary tissue of gestational ages 6 and 10–12 weeks. One of the lesions displayed endocrine differentiation and immunoreactivities typical for FSCs. The origin of these two lesions was concluded to be the FSC as a pluripotent adult stem cell [44]. In a different study, 3 benign oncocytic neoplasms, coined ‘‘spindle cell oncocytoma’’, showed no ultrastructural follicular formation, however, based on immunoreactivity for vimentin, S-100, and galectin-3, the investigators concluded that the benign neoplasms had a FSC derivation [23]. Despite the numerous studies on FSCs, there is no conclusive evidence to define FSCs as true pituitary stem cells. Morphological similarities between the FSCs and pituitary stem cells are suggestive of their candidacy, however definitive evidence is needed to show that these cells are indeed able to differentiate into functional hormonal cells.
Marginal cells The organogenesis of the pituitary is an extensive topic that will not be covered in this review. However, it is important to note that during embryogenesis, progenitor cells are present in the marginal zone close to the pituitary cleft [1].
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Marginal cells are located in the pituitary cleft and in the marginal zone of the adult pituitary. These cells possess immature structural characteristics that are very similar to those seen in follicular cells. It should be noted that granules have not been identified in marginal cells, and there is a large number of free ribosomes and polyribosomes within the marginal cells [45, 46]. To our knowledge, there is only 1 published report that supports the role of marginal cells as putative pituitary stem cells. This study showed that, regardless of age, nestin immunoreactivity was detected in cells that lined the pituitary cleft adjacent to the marginal zone [43]. There is a paucity of studies investigating the potential role for marginal cells as pituitary stem cells. Stem cell markers suggest that marginal cells may be a source of pituitary stem cells. However, future studies should investigate the selfrenewal capacity of marginal cells and their ability to differentiate into hormone secreting pituitary cells.
Side population cells The Hoescht-stained side populations of stem cells were first discovered in 1996. This technique is based on the assumption that stem cells extrude harmful substances. When murine bone marrow cells incubated with Hoescht33342, a DNA-binding dye, were analyzed with a fluorescence activated cell sorter at two emission wavelengths, it was found that a side population of cells in the double emission plot contained phenotypic markers of multipotential hematopoetic stem cells [47]. This plot showed a side population that extruded the dye, and a main population that did not. Since its advent in 1996, this technique has been used to identify side population of stem cell-like cells in many tissues including the brain [48]. The side-population technique was also used to identify potential pituitary stem cells. Using this technique it was found that 71 % of these cells expressed Sca-1, a stem cell marker [9]. Moreover, this pituitary side population expressed Nestin, Bmi-1, and prominin-1, markers of neural stem cells and hematopoetic stem cells. It is important to note that this population did not express other markets of hematopoietic stem cells such as CD434 or c-kit. Oct-4 and Nanog, which are expressed in embryonic stem cells, were also expressed in the pituitary side population. The pituitary side population also expressed high levels of Notch1 and other markers that function in stem cell homeostasis and early pituitary embryogenesis. Moreover, it was found that the side population pituitary cells exclusively expressed Lhx4, a transcription factor that is important in the early embyrogenesis of the adenohypophysis. The main population of cells did not express Lhx4, but rather expressed Lhx3, suggesting that the side population can easily be identified as
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high levels of Lhx4 likely function to maintain the undifferentiated state of progenitor cells [9]. The pituitary side population of cells express many genes that regulate stem-cell like phenotype. Nevertheless, there is no conclusive evidence that these cells are true stem cells as their capacity for self-renewal and pluripotency has yet to be investigated. Future studies should be performed to clearly identify these fundamental properties and to also delineate which cells of the heterogenous side population may be the source of pituitary stem cells.
Sox2-positive/Sox9-negative cells Sox2 is a crucial transcription factor required for the function of multiple stem cell populations, especially those within the developing CNS [49, 50]. Sox2-positive and Stem cell antingen-1 (Sca1)-positive cells present within Rathke’s Pouch during development downregulate Sox2 and Sca1 as they differentiate to form the adult anterior pituitary. However, a residual level (3 %) of Sox2-positive/Sca-1-positive stem cells persist within the adult pituitary [10]. These Sox2positive cells line the pituitary cleft, but are also scattered throughout the parenchyma. When cultured in vitro they form pituispheres capable of proliferation, with 0.03–0.05 % of cells self-renewing into secondary spheres [10]. The nonrenewing cells downregulate Sox2 and Sca1 but express Sox9, nestin, and S100-B as they commit along particular cell lineages [10, 51]. Committed Sox2-positive/Sox9positive cells differentiate into all 5 types of hormoneproducing cells as well as S100-B expressing FSCs. Spheres were not restricted to one type of hormone-producing cell suggesting that the progenitor cells remain multipotent [10]. The infrequent proliferation of Sox2-positive/Sox9positive cells, along with their S100B expression, suggests that these cells represent transient-amplifying cells committed to a specific pituitary cell type [52]. In contrast, the 1 % of adult Sox2-positive cells that do not express Sox9 are non-hormone producing, divide slowly, express stem cell antigen-1, differentiate, and are able to generate secondary pituispheres [10, 53]. Although these are characteristics of stem cell populations, five passages are classically needed to show that a given cell type is capable self-renewal. It will be important for further studies to characterize the self-renewal capacity of Sox2-positive/Sox9-negative pituicytes in order to assess whether they are multipotent progenitors or a population of self-renewing pituitary stem cells.
GFRa2/Prop1-positive stem (GPS) cells Glial cell line-derived neurotrophic factor receptor alpha 2 (GFRa2) is a neurturin (NTN) receptor found expressed on
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0.9 % of adult anterior pituitary cells lining the pituitary cleft [54]. In addition to expressing many well-established stem cells markers (Oct4, SSEA4, Sox2, and Sox9), these cells also express Prophet of Pit1 (Prop1), a pituitaryspecific transcription factor required for pituitary development [55]. These GFRa2-positive/Prop1-positive stem (GPS) cells are slowly cycling cells that generate secondary pituispheres in vitro [56, 57]. It has been proposed that the vimentin-positive cells surrounding the GPS cells within the cleft serve to confine GPS cells within their niche. However, in conditions of high NTN concentrations outside this niche, GPS cells migrate out and differentiate into Cdk4-positive/Oct4-negative/Prop1-negative/GFPa2negative transient amplifying pituicytes [56]. This expression profile is thought to represent a transition from the differentiation-inhibiting effects of Prop1 towards the differentiation-promoting control of Cdk4 [58]. GPS-derived cells have the capacity to differentiate into somatotrophs, lactotrophs, thyrotrophs, corticotrophs, gonadotrophs, and folliculostellate cells [56]. This subpopulation of anterior pituitary cells is likely a group of stem/progenitor cells as they are agranular, express stem cell markers (Oct4, SSEA4, Prop1, and Sox2), show limited self-renewal, slowly replicate, and differentiate into all 5 types of hormone producing pituitary cells. Interestingly, the GPS expression profile of Sox2, Sox9, E-cadherin, and S100-B is similar the Sox2-positive/ Sox9-negative transient amplifying cells. Therefore, GPS cells are likely a set of adult progenitor cells that proliferate within an exclusive niche, rather than a population of true pituitary stem cells. However, as with Sox2-positive/Sox9negative cells, a more extensive assessment of GPS cell self-renewal capabilities is necessary to characterize their phenotype.
Pituitary stem cells and pituitary adenomas The identification of a definitive pituitary stem cell could have major contributions to skullbase neurosurgery and pituitary pathology. It is thought that aberrant proliferation of pituitary stem cells occurs after an abrupt change in the pituitary milieu leading to the formation of pituitary adenomas [8, 12]. To our knowledge only 1 animal study has investigated the role of potential stem cells in the development of pituitary tumors. This study used genetic techniques to study the role that nestin positive cells play in tumorigenesis. Mice carrying one functional retinoblastoma allele (Rb+/-) were crossed with nestin and GFP- positive mice [11]. The progeny of the cross mice with predominantly melanocyte stimulating hormone (MSH) tumors. None of the tumor cells costained with nestin, however, nestin-positive cells that
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expressed Lhx3 and SOX-2 encapsulated the tumors. Based on anatomical proximity, the authors concluded that nestin positive cells contribute to the initiation of MSH-positive adenomas [11]. If the hypothesis regarding pituitary tumorigenesis is valid, the implications for pituitary adenoma treatments are significant. Unless the aberrant pituitary stem cells are removed then an indefinite risk exists for recurrence of the tumor even if ‘‘gross total resection’’ of the adenoma is surgically achieved. Moreover, if a unique cell surface marker to the aberrant stem cell is identified, then it would be possible to label the cells with an antibody and use immunohistochemical analyses to ensure that the stem cell is removed and to secure clear surgical margins. In summary, the pituitary is a dynamic organ that undergoes considerable changes in response to physiological stimuli and pituitary microenvironment changes. These changes are thought to be mediated by the differentiation of pituitary stem cells. Unlike neural stem cells, pituitary stem cells have not been clearly been delineated to a certain cell type, and many potential candidates exist. The major candidates include the chromophobes cell types, folliculostellate cells and marginal cells,, the side population cells, SOX2-positive/SOX9-negative cells, and GPS cells. There is insufficient evidence to conclude that a specific cell type is definitive of a true pituitary stem cell. There has been a considerable amount of studies investigating the potential of folliculostellate cells to act as pituitary stem cells. We believe that the current evidence suggests that the folliculostellate cells are the most likely cell type to represent pituitary stem cells, however, future studies need to clearly elucidate the pluripotent capacity of FSCs. Moreover, emerging evidence about the candidacy of GPS cells and SOX2-positive/SOX9negative cells needs to be investigated further. The implications of the discovery of pituitary stem cells are considerable, and could possibly help improve neurosurgical and medical management of pituitary adenomas. Acknowledgments Authors are grateful to the Jarislowsky and Lloyd Carr-Harris Foundations for their generous support. Conflict of interest
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