Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pituitary stem cells: past, present and future perspectives

Nature Reviews Endocrinology volume 20, pages 77–92 (2024)Cite this article

Subjects

Abstract

Pituitary cells that express the transcription factor SOX2 are stem cells because they can self-renew and differentiate into multiple pituitary hormone-producing cell types as organoids. Wounding and physiological challenges can activate pituitary stem cells, but cell numbers are not fully restored, and the ability to mobilize stem cells decreases with increasing age. The basis of these limitations is still unknown. The regulation of stem cell quiescence and activation involves many different signalling pathways, including those mediated by WNT, Hippo and several cytokines; more research is needed to understand the interactions between these pathways. Pituitary organoids can be formed from human or mouse embryonic stem cells, or from human induced pluripotent stem cells. Human pituitary organoid transplantation is sufficient to induce corticosterone release in hypophysectomized mice, raising the possibility of therapeutic applications. Today, pituitary organoids have the potential to assess the role of individual genes and genetic variants on hormone production ex vivo, providing an important tool for the advancement of exciting frontiers in pituitary stem cell biology and pituitary organogenesis. In this article, we provide an overview of notable discoveries in pituitary stem cell function and highlight important areas for future research.

Key points

  • The cells of the anterior pituitary gland have a low turnover rate, and the tissue has a limited regenerative capacity.

  • Pituitary stem cells secrete factors, such as WNT and Hippo, that initiate proliferation in adjacent cells; the recipient cells are probably guided to differentiate into specific hormone-producing cell types by hypothalamic input and/or end organ feedback.

  • Organoids and 2D cultures derived from embryonic stem cells and induced pluripotent stem cell cultures show promise as tools for the study of differentiation ex vivo.

  • Stem cells are known to exist in pituitary tumours, but the roles of these cells in tumour initiation, progression, recurrence and resistance to pharmacological therapy need to be further elucidated.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Anatomy of the rodent pituitary gland, base of the hypothalamus and supporting vasculature.
Fig. 2: Pituitary development and stem cells.
Fig. 3: Pituitary organoid differentiation from mouse and human ES cells requires a variety of growth factors and inhibitors.
Fig. 4: Differentiation of human pituitary cells from iPS cells in monolayer cultures.

Similar content being viewed by others

References

  1. Bosch, I. A. L., Katugampola, H. & Dattani, M. T. Congenital hypopituitarism during the neonatal period: epidemiology, pathogenesis, therapeutic options, and outcome. Front. Pediatr. 8, 600962 (2020).

    Article  Google Scholar 

  2. Daly, A. Z. & Camper, S. A. in Susan, W. & Seth, B. (eds) Masterclass in Neuroendocrinology vol. 9, 129–177 (Springer, 2020).

  3. Davis, S. W. et al. β-Catenin is required in the neural crest and mesencephalon for pituitary gland organogenesis. BMC Dev. Biol. 16, 16 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Horiguchi, K. et al. S100β-positive cells of mesenchymal origin reside in the anterior lobe of the embryonic pituitary gland. PLoS One 11, e0163981 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ueharu, H. et al. Gene tracing analysis reveals the contribution of neural crest-derived cells in pituitary development. J. Anat. 230, 373–380 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Kato, Y., Yoshida, S. & Kato, T. New insights into the role and origin of pituitary S100β-positive cells. Cell Tissue Res. 386, 227–237 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Ikeda, H., Suzuki, J., Sasano, N. & Niizuma, H. The development and morphogenesis of the human pituitary gland. Anat. Embryol. 178, 327–336 (1988).

    Article  CAS  Google Scholar 

  8. Cheung, L. Y. M. & Camper, S. A. in Reference Module in Biomedical Sciences (Elsevier, 2018).

  9. Ward, R. D. et al. Role of PROP1 in pituitary gland growth. Mol. Endocrinol. 19, 698–710 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Japon, M. A., Rubinstein, M. & Low, M. J. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J. Histochem. Cytochem. 42, 1117–1125 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Yamada, M. et al. Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene. Proc. Natl Acad. Sci. USA 94, 10862–10867 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Godfrey, P. et al. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat. Genet. 4, 227–232 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Carreno, G. et al. Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors. Development 144, 3289–3302 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Treier, M. et al. Multistep signaling requirements for pituitary organogenesis in vivo. Genes Dev. 12, 1691–1704 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cheung, L. et al. NOTCH activity differentially affects alternative cell fate acquisition and maintenance. eLife 7, e33318 (2018). Notch signalling has different roles at distinct stages of pituitary development.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lodge, E. J. et al. Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade. eLife 8, e43996 (2019). Hippo signalling is an important regulator of pituitary gland growth and differentiation.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Willis, T. L., Lodge, E. J., Andoniadou, C. L. & Yianni, V. Cellular interactions in the pituitary stem cell niche. Cell Mol. Life Sci. 79, 612 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Le Tissier, P. R., Murray, J. F. & Mollard, P. A new perspective on regulation of pituitary plasticity: the network of SOX2-positive cells may coordinate responses to challenge. Endocrinology 163, bqac089 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yoshida, S., Kato, T. & Kato, Y. EMT involved in migration of stem/progenitor cells for pituitary development and regeneration. J. Clin. Med. 5, 43 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Nolan, L. A., Kavanagh, E., Lightman, S. L. & Levy, A. Anterior pituitary cell population control: basal cell turnover and the effects of adrenalectomy and dexamethasone treatment. J. Neuroendocrinol. 10, 207–215 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Borrelli, E., Heyman, R. A., Arias, C., Sawchenko, P. E. & Evans, R. M. Transgenic mice with inducible dwarfism. Nature 339, 538–541 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Fu, Q. et al. The adult pituitary shows stem/progenitor cell activation in response to injury and is capable of regeneration. Endocrinology 153, 3224–3235 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Waite, E. et al. Different degrees of somatotroph ablation compromise pituitary growth hormone cell network structure and other pituitary endocrine cell types. Endocrinology 151, 234–243 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Yoshimura, F., Harumiya, K., Ishikawa, H. & Otsuka, Y. Differentiation of isolated chromophobes into acidophils or basophils when transplanted into the hypophysiotrophic area of hypothalamus. Endocrinol. Jpn 16, 531–540 (1969).

    Article  CAS  PubMed  Google Scholar 

  25. Shiino, M., Ishikawa, H. & Rennels, E. G. In vitro and in vivo studies on cytodifferentiation of pituitary clonal cells derived from the epithelium of Rathke’s pouch. Cell Tissue Res. 181, 473–485 (1977).

    Article  CAS  PubMed  Google Scholar 

  26. Rinehart, J. F. & Farquhar, M. G. Electron microscopic studies of the anterior pituitary gland. J. Histochem. Cytochem. 1, 93–113 (1953).

    Article  CAS  PubMed  Google Scholar 

  27. Vila-Porcile, E. The network of the folliculo-stellate cells and the follicles of the adenohypophysis in the rat (pars distalis) [French]. Z. Zellforsch. Mikrosk. Anat. 129, 328–369 (1972).

    Article  CAS  PubMed  Google Scholar 

  28. Shirasawa, N. & Yoshimura, F. Immunohistochemical and electron microscopical studies of mitotic adenohypophysial cells in different ages of rats. Anat. Embryol. 165, 51–61 (1982).

    Article  CAS  Google Scholar 

  29. Lepore, D. A. et al. Identification and enrichment of colony-forming cells from the adult murine pituitary. Exp. Cell Res. 308, 166–176 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Bauer, K. Carnosine and homocarnosine, the forgotten, enigmatic peptides of the brain. Neurochem. Res. 30, 1339–1345 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Lepore, D. A. et al. Survival and differentiation of pituitary colony-forming cells in vivo. Stem Cell 25, 1730–1736 (2007).

    Article  CAS  Google Scholar 

  32. Chen, J. et al. The adult pituitary contains a cell population displaying stem/progenitor cell and early embryonic characteristics. Endocrinology 146, 3985–3998 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Chen, J. et al. Pituitary progenitor cells tracked down by side population dissection. Stem Cell 27, 1182–1195 (2009).

    Article  CAS  Google Scholar 

  34. Fu, Q. & Vankelecom, H. Regenerative capacity of the adult pituitary: multiple mechanisms of lactotrope restoration after transgenic ablation. Stem Cell Dev. 21, 3245–3257 (2012).

    Article  CAS  Google Scholar 

  35. Fauquier, T., Rizzoti, K., Dattani, M., Lovell-Badge, R. & Robinson, I. C. SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc. Natl Acad. Sci. USA 105, 2907–2912 (2008). SOX2-expressing cells were demonstrated to have the properties of pituitary stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martello, G. & Smith, A. The nature of embryonic stem cells. Annu. Rev. Cell Dev. Biol. 30, 647–675 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Fletcher, P. A. et al. The astroglial and stem cell functions of adult rat folliculostellate cells. Glia 71, 205–228 (2022).

    Article  PubMed  Google Scholar 

  38. Gremeaux, L., Fu, Q., Chen, J. & Vankelecom, H. Activated phenotype of the pituitary stem/progenitor cell compartment during the early-postnatal maturation phase of the gland. Stem Cell Dev. 21, 801–813 (2012).

    Article  CAS  Google Scholar 

  39. Willems, C. et al. Regeneration in the pituitary after cell-ablation injury: time-related aspects and molecular analysis. Endocrinology 157, 705–721 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Vennekens, A. et al. Interleukin-6 is an activator of pituitary stem cells upon local damage, a competence quenched in the aging gland. Proc. Natl Acad. Sci. USA 118, e2100052118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Andoniadou, C. L. et al. Sox2+ stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell 13, 433–445 (2013). Lineage tracing demonstrates that all hormone-producing cell types are derived from SOX2-expressing cells in mice.

    Article  CAS  PubMed  Google Scholar 

  44. Rizzoti, K., Akiyama, H. & Lovell-Badge, R. Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand. Cell Stem Cell 13, 419–432 (2013). Ablation of pituitary target organs was shown to mobilize stem cells to proliferate and differentiate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Roose, H. et al. Major depletion of SOX2+ stem cells in the adult pituitary is not restored which does not affect hormonal cell homeostasis and remodelling. Sci. Rep. 7, 16940 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pérez Millán, M. I., Brinkmeier, M. L., Mortensen, A. H. & Camper, S. A. PROP1 triggers epithelial-mesenchymal transition-like process in pituitary stem cells. eLife 5, e14470 (2016). PROP1 is expressed in stem cells during development and is required to establish a robust stem cell pool and to induce an epithelial-to-mesenchymal-like transition.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Himes, A. D. & Raetzman, L. T. Premature differentiation and aberrant movement of pituitary cells lacking both Hes1 and Prop1. Dev. Biol. 325, 151–161 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Horiguchi, K. et al. Isolation and characterisation of CD9-positive pituitary adult stem/progenitor cells in rats. Sci. Rep. 8, 5533 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Horiguchi, K. et al. Differentiation of stem progenitor CD9/SOX2-positive cells is promoted with increased prolactin-producing and endothelial cells in the pituitary. J. Reprod. Dev. 68, 278–286 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yoshida, S. et al. Cell type-specific localization of Ephs pairing with ephrin-B2 in the rat postnatal pituitary gland. Cell Tissue Res. 370, 99–112 (2017).

    Article  CAS  PubMed  Google Scholar 

  51. Yoshida, S. et al. Localization of juxtacrine factor ephrin-B2 in pituitary stem/progenitor cell niches throughout life. Cell Tissue Res. 359, 755–766 (2015).

    Article  CAS  PubMed  Google Scholar 

  52. Yoshida, S. et al. Expression and localization of tight junction-related proteins in adult rat pituitary stem/progenitor cell niches. J. Reprod. Dev. 68, 225–231 (2022). Multiple markers of the pituitary stem cell niche were identified.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cheung, L. Y. M. et al. Single-cell RNA sequencing reveals novel markers of male pituitary stem cells and hormone-producing cell types. Endocrinology 159, 3910–3924 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cheung, L. Y. M. & Camper, S. A. PROP1-dependent retinoic acid signaling regulates developmental pituitary morphogenesis and hormone expression. Endocrinology 161, bqaa002 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Mayran, A. et al. Pioneer and nonpioneer factor cooperation drives lineage specific chromatin opening. Nat. Commun. 10, 3807 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ruf-Zamojski, F. et al. Single nucleus multi-omics regulatory landscape of the murine pituitary. Nat. Commun. 12, 2677 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, Z. et al. Single nucleus transcriptome and chromatin accessibility of postmortem human pituitaries reveal diverse stem cell regulatory mechanisms. Cell Rep. 38, 110467 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ho, Y. et al. Single-cell transcriptomic analysis of adult mouse pituitary reveals sexual dimorphism and physiologic demand-induced cellular plasticity. Protein Cell 11, 565–583 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhang, S. et al. Single-cell transcriptomics identifies divergent developmental lineage trajectories during human pituitary development. Nat. Commun. 11, 5275 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Allensworth-James, M. et al. Control of the anterior pituitary cell lineage regulator POU1F1 by the stem cell determinant musashi. Endocrinology 162, bqaa245 (2021).

    Article  PubMed  Google Scholar 

  61. Laporte, E. et al. Decoding the activated stem cell phenotype of the neonatally maturing pituitary. eLife 11, e75742 (2022). The cytokine IL-6 has a role in stem cell activation in vitro after injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Finnell, R. H. et al. Gene environment interactions in the etiology of neural tube defects. Front. Genet. 12, 659612 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mohanty, V. et al. Folate receptor alpha upregulates Oct4, Sox2 and Klf4 and downregulates miR-138 and miR-let-7 in cranial neural crest cells. Stem Cell 34, 2721–2732 (2016).

    Article  CAS  Google Scholar 

  64. Monick, S. et al. A phenotypic switch of differentiated glial cells to dedifferentiated cells is regulated by folate receptor α. Stem Cell 37, 1441–1454 (2019).

    Article  CAS  Google Scholar 

  65. Davis, S. W., Keisler, J. L., Perez-Millan, M. I., Schade, V. & Camper, S. A. All hormone-producing cell types of the pituitary intermediate and anterior lobes derive from prop1-expressing progenitors. Endocrinology 157, 1385–1396 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Stanisavljevic, J., Porta-de-la-Riva, M., Batlle, R., de Herreros, A. G. & Baulida, J. The p65 subunit of NF-κB and PARP1 assist Snail1 in activating fibronectin transcription. J. Cell Sci. 124, 4161–4171 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Villarejo, A., Cortes-Cabrera, A., Molina-Ortiz, P., Portillo, F. & Cano, A. Differential role of Snail1 and Snail2 zinc fingers in E-cadherin repression and epithelial to mesenchymal transition. J. Biol. Chem. 289, 930–941 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Horiguchi, K. et al. Expression of Slug in S100β-protein-positive cells of postnatal developing rat anterior pituitary gland. Cell Tissue Res. 363, 513–524 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Vandewalle, C. et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 33, 6566–6578 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Winningham, A. H. & Camper, S. A. Pituitary stem cell regulation by Zeb2 and BMP signaling. Endocrinology 164, bqad016 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chen, Z. F. & Behringer, R. R. Twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 9, 686–699 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Vankelecom, H. Pituitary stem/progenitor cells: embryonic players in the adult gland? Eur. J. Neurosci. 32, 2063–2081 (2010).

    Article  PubMed  Google Scholar 

  74. Daly, A. Z. et al. Multi-omic profiling of pituitary thyrotropic cells and progenitors. BMC Biol. 19, 76 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Aninye, I. O., Matsumoto, S., Sidhaye, A. R. & Wondisford, F. E. Circadian regulation of Tshb gene expression by Rev-Erbα (NR1D1) and nuclear corepressor 1 (NCOR1). J. Biol. Chem. 289, 17070–17077 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Janssen, J. S. et al. A rexinoid antagonist increases the hypothalamic-pituitary-thyroid set point in mice and thyrotrope cells. Mol. Cell Endocrinol. 339, 1–6 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Nakajima, Y. et al. NR4A1 (Nur77) mediates thyrotropin-releasing hormone-induced stimulation of transcription of the thyrotropin β gene: analysis of TRH knockout mice. PLoS One 7, e40437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Raetzman, L. T. et al. Developmental regulation of Notch signaling genes in the embryonic pituitary: Prop1 deficiency affects Notch2 expression. Dev. Biol. 265, 329–340 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Lee, Y., Kim, J. M. & Lee, E. J. Functional expression of CXCR4 in somatotrophs: CXCL12 activates GH gene, GH production and secretion, and cellular proliferation. J. Endocrinol. 199, 191–199 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Horiguchi, K. et al. Expression of chemokine CXCL12 and its receptor CXCR4 in folliculostellate (FS) cells of the rat anterior pituitary gland: the CXCL12/CXCR4 axis induces interconnection of FS cells. Endocrinology 153, 1717–1724 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Sarkar, D. K., Kim, K. H. & Minami, S. Transforming growth factor-beta 1 messenger RNA and protein expression in the pituitary gland: its action on prolactin secretion and lactotropic growth. Mol. Endocrinol. 6, 1825–1833 (1992).

    CAS  PubMed  Google Scholar 

  82. Ericson, J., Norlin, S., Jessell, T. M. & Edlund, T. Integrated FGF and BMP signaling controls the progression of progenitor cell differentiation and the emergence of pattern in the embryonic anterior pituitary. Development 125, 1005–1015 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Takuma, N. et al. Formation of Rathke’s pouch requires dual induction from the diencephalon. Development 125, 4835–4840 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Davis, S. W. & Camper, S. A. Noggin regulates Bmp4 activity during pituitary induction. Dev. Biol. 305, 145–160 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. De Moerlooze, L. et al. An important role for the IIIb isoform of fibroblast growth factor receptor 2 (FGFR2) in mesenchymal-epithelial signalling during mouse organogenesis. Development 127, 483–492 (2000).

    Article  PubMed  Google Scholar 

  86. Ohuchi, H. et al. FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem. Biophys. Res. Commun. 277, 643–649 (2000).

    Article  CAS  PubMed  Google Scholar 

  87. Norlin, S., Nordstrom, U. & Edlund, T. Fibroblast growth factor signaling is required for the proliferation and patterning of progenitor cells in the developing anterior pituitary. Mech. Dev. 96, 175–182 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Osmundsen, A. M., Keisler, J. L., Taketo, M. M. & Davis, S. W. Canonical WNT signaling regulates the pituitary organizer and pituitary gland formation. Endocrinology 158, 3339–3353 (2017).

    Article  CAS  PubMed  Google Scholar 

  89. Mortensen, A. H., Schade, V., Lamonerie, T. & Camper, S. A. Deletion of OTX2 in neural ectoderm delays anterior pituitary development. Hum. Mol. Genet. 24, 939–953 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Matsumoto, R. et al. Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells. J. Clin. Invest. 130, 641–654 (2020).

    Article  PubMed  Google Scholar 

  91. Haston, S. et al. MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma. Development 144, 2141–2152 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Gualtieri, A. et al. Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans. Nat. Commun. 12, 2028 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Nantie, L. B., Himes, A. D., Getz, D. R. & Raetzman, L. T. Notch signaling in postnatal pituitary expansion: proliferation, progenitors, and cell specification. Mol. Endocrinol. 28, 731–744 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Zhu, X., Tollkuhn, J., Taylor, H. & Rosenfeld, M. G. Notch-dependent pituitary SOX2+ stem cells exhibit a timed functional extinction in regulation of the postnatal gland. Stem Cell Rep. 5, 1196–1209 (2015).

    Article  CAS  Google Scholar 

  95. Edwards, W., Nantie, L. B. & Raetzman, L. T. Identification of a novel progenitor cell marker, grainyhead-like 2 in the developing pituitary. Dev. Dyn. 245, 1097–1106 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kita, A. et al. Hes1 and Hes5 control the progenitor pool, intermediate lobe specification, and posterior lobe formation in the pituitary development. Mol. Endocrinol. 21, 1458–1466 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Potok, M. A. et al. WNT signaling affects gene expression in the ventral diencephalon and pituitary gland growth. Dev. Dyn. 237, 1006–1020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Youngblood, J. L., Coleman, T. F. & Davis, S. W. Regulation of pituitary progenitor differentiation by β-catenin. Endocrinology 159, 3287–3305 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Gaston-Massuet, C. et al. Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc. Natl Acad. Sci. USA 108, 11482–11487 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Gonzalez-Meljem, J. M. et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat. Commun. 8, 1819 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Dasen, J. S. et al. Temporal regulation of a paired-like homeodomain repressor/TLE corepressor complex and a related activator is required for pituitary organogenesis. Genes Dev. 15, 3193–3207 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Olson, L. E. et al. Homeodomain-mediated β-catenin-dependent switching events dictate cell-lineage determination. Cell 125, 593–605 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Russell, J. P. et al. Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells. eLife 10, e59142 (2021). WNT signalling is an important regulator of pituitary growth and differentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Treier, M. et al. Hedgehog signaling is required for pituitary gland development. Development 128, 377–386 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Muthu, V., Eachus, H., Ellis, P., Brown, S. & Placzek, M. Rx3 and Shh direct anisotropic growth and specification in the zebrafish tuberal/anterior hypothalamus. Development 143, 2651–2663 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lodge, E. J., Russell, J. P., Patist, A. L., Francis-West, P. & Andoniadou, C. L. Expression analysis of the hippo cascade indicates a role in pituitary stem cell development. Front. Physiol. 7, 114 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Boopathy, G. T. K. & Hong, W. Role of hippo pathway-YAP/TAZ signaling in angiogenesis. Front. Cell Dev. Biol. 7, 49 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Langlais, D., Couture, C., Kmita, M. & Drouin, J. Adult pituitary cell maintenance: lineage-specific contribution of self-duplication. Mol. Endocrinol. 27, 1103–1112 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Castrique, E., Fernandez-Fuente, M., Le Tissier, P., Herman, A. & Levy, A. Use of a prolactin-Cre/ROSA-YFP transgenic mouse provides no evidence for lactotroph transdifferentiation after weaning, or increase in lactotroph/somatotroph proportion in lactation. J. Endocrinol. 205, 49–60 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nolan, L. A. & Levy, A. A population of non-luteinising hormone/non-adrenocorticotrophic hormone-positive cells in the male rat anterior pituitary responds mitotically to both gonadectomy and adrenalectomy. J. Neuroendocrinol. 18, 655–661 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Laporte, E., De Vriendt, S., Hoekx, J. & Vankelecom, H. Interleukin-6 is dispensable in pituitary normal development and homeostasis but needed for pituitary stem cell activation following local injury. Front. Endocrinol. 13, 1092063 (2022).

    Article  Google Scholar 

  112. Alim, Z. et al. Gonadotrope plasticity at cellular and population levels. Endocrinology 153, 4729–4739 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hodson, D. J. et al. Existence of long-lasting experience-dependent plasticity in endocrine cell networks. Nat. Commun. 3, 605 (2012).

    Article  PubMed  Google Scholar 

  114. Kim, S. Y. Diagnosis and treatment of hypopituitarism. Endocrinol. Metab. 30, 443–455 (2015).

    Article  CAS  Google Scholar 

  115. Suga, H. et al. Self-formation of functional adenohypophysis in three-dimensional culture. Nature 480, 57–62 (2011). In vitro differentiation of mouse ES cells into pituitary cells was able to rescue cortisol deficiency in hypophysectomized mice.

    Article  CAS  PubMed  Google Scholar 

  116. Dincer, Z. et al. Specification of functional cranial placode derivatives from human pluripotent stem cells. Cell Rep. 5, 1387–1402 (2013). Human ES cells and iPS cells were differentiated into anterior pituitary cells in culture.

    Article  CAS  PubMed  Google Scholar 

  117. Ozone, C. et al. Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells. Nat. Commun. 7, 10351 (2016). Multi-omics profiling of human pituitary cells at different ages.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zimmer, B. et al. Derivation of diverse hormone-releasing pituitary cells from human pluripotent stem cells. Stem Cell Rep. 6, 858–872 (2016).

    Article  CAS  Google Scholar 

  119. Kasai, T. et al. Hypothalamic contribution to pituitary functions is recapitulated in vitro using 3D-cultured human iPS cells. Cell Rep. 30, 18–24.e5 (2020).

    Article  CAS  PubMed  Google Scholar 

  120. Cox, B. et al. Organoids from pituitary as a novel research model toward pituitary stem cell exploration. J. Endocrinol. 240, 287–308 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Cheng, Y. et al. Retinoic acid and dexamethasone induce differentiation and maturation of somatotroph cells at different stages in vitro. Endocr. J. 58, 177–184 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Yoshida, S. et al. Retinoic acid signalling is a candidate regulator of the expression of pituitary-specific transcription factor Prop1 in the developing rodent pituitary. J. Neuroendocrinol. 30, e12570 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Shao, Y. & Fu, J. Engineering multiscale structural orders for high-fidelity embryoids and organoids. Cell Stem Cell 29, 722–743 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Barker, N. et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Zomer, A. et al. Intravital imaging of cancer stem cell plasticity in mammary tumors. Stem Cell 31, 602–606 (2013).

    Article  CAS  Google Scholar 

  127. Griffin, J. D. & Lowenberg, B. Clonogenic cells in acute myeloblastic leukemia. Blood 68, 1185–1195 (1986).

    Article  CAS  PubMed  Google Scholar 

  128. Holczbauer, A. et al. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 145, 221–231 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Friedmann-Morvinski, D. & Verma, I. M. Dedifferentiation and reprogramming: origins of cancer stem cells. EMBO Rep. 15, 244–253 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).

    Article  CAS  PubMed  Google Scholar 

  131. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J. & Clarke, M. F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    Article  CAS  PubMed  Google Scholar 

  133. Schelin, U., Lundin, P. M. & Bartholdson, L. Light and electron microscopic studies on an autonomous stilbestrol-induced pituitary tumor in rats. Endocrinology 75, 893–900 (1964).

    Article  CAS  PubMed  Google Scholar 

  134. Rovit, R. L. & Duane, T. D. Eye signs in patients with Cushing’s syndrome and pituitary tumors: some observations related to chromophobe tumors and hyperadrenalism. Tr. Am. Ophth. Soc. 65, 52–93 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Capen, C. C., Martin, S. L. & Koestner, A. Neoplasms in the adenohypophysis of dogs. Path. Vet. 4, 301–325 (1967).

    CAS  Google Scholar 

  136. Prieto-Vila, M., Takahashi, R. U., Usuba, W., Kohama, I. & Ochiya, T. Drug resistance driven by cancer stem cells and their niche. Int. J. Mol. Sci. 18, 2574 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Sarkar, A. & Hochedlinger, K. The sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell 12, 15–30 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Clevers, H. The cancer stem cell: premises, promises and challenges. Nat. Med. 17, 313–319 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Kim, W. T. & Ryu, C. J. Cancer stem cell surface markers on normal stem cells. BMB Rep. 50, 285–298 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Nys, C. et al. Exploring stem cell biology in pituitary tumors and derived organoids. Endocr. Relat. Cancer 29, 427–450 (2022).

    Article  CAS  PubMed  Google Scholar 

  141. Ho, K. et al. Pituitary neoplasm nomenclature workshop: does adenoma stand the test of time? J. Endocr. Soc. 5, bvaa205 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Mertens, F. et al. Pituitary tumors contain a side population with tumor stem cell-associated characteristics. Endocr. Relat. Cancer 22, 481–504 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Xu, Q. et al. Isolation of tumour stem-like cells from benign tumours. Br. J. Cancer 101, 303–311 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Hosoyama, T. et al. A postnatal Pax7 progenitor gives rise to pituitary adenomas. Genes. Cancer 1, 388–402 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Yunoue, S. et al. Identification of CD133+ cells in pituitary adenomas. Neuroendocrinology 94, 302–312 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Chen, L. et al. Evidence of brain tumor stem progenitor-like cells with low proliferative capacity in human benign pituitary adenoma. Cancer Lett. 349, 61–66 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Wurth, R. et al. Phenotypical and pharmacological characterization of stem-like cells in human pituitary adenomas. Mol. Neurobiol. 54, 4879–4895 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Peverelli, E. et al. Dopamine receptor type 2 (DRD2) and somatostatin receptor type 2 (SSTR2) agonists are effective in inhibiting proliferation of progenitor/stem-like cells isolated from nonfunctioning pituitary tumors. Int. J. Cancer 140, 1870–1880 (2017).

    Article  CAS  PubMed  Google Scholar 

  149. Manoranjan, B. et al. The identification of human pituitary adenoma-initiating cells. Acta Neuropathol. Commun. 4, 125 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Wurth, R., Thellung, S., Corsaro, A., Barbieri, F. & Florio, T. Experimental evidence and clinical implications of pituitary adenoma stem cells. Front. Endocrinol. 11, 54 (2020).

    Article  Google Scholar 

  151. Nakayama, K. et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors. Cell 85, 707–720 (1996).

    Article  CAS  PubMed  Google Scholar 

  152. Moncho-Amor, V. et al. SOX2 is required independently in both stem and differentiated cells for pituitary tumorigenesis in p27-null mice. Proc. Natl Acad. Sci. USA 118, e2017115118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Marques, P., Grossman, A. B. & Korbonits, M. The tumour microenvironment of pituitary neuroendocrine tumours. Front. Neuroendocrinol. 58, 100852 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Wimmer, R. A. et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565, 505–510 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Vahsen, B. F. et al. Human iPSC co-culture model to investigate the interaction between microglia and motor neurons. Sci. Rep. 12, 12606 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Beauchamp, P. et al. 3D co-culture of hiPSC-derived cardiomyocytes with cardiac fibroblasts improves tissue-like features of cardiac spheroids. Front. Mol. Biosci. 7, 14 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Suga, H. Making pituitary hormone-producing cells in a dish. Endocr. J. 63, 669–680 (2016).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge funding from the National Institutes of Health (R01HD097096 to S.A.C. and R03AG072221 to L.Y.M.C.) and from Agencia PICT 2021 162 and PICT 2018 4239 to M.I.P.M.

Author information

Authors and Affiliations

  1. Institute of Bioscience, Biotechnology and Translational Biology (IB3-UBA), University of Buenos Aires, Buenos Aires, Argentina

    María Inés Pérez Millán, Florencia Mercogliano & Maria Andrea Camilletti

  2. Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA

    Leonard Y. M. Cheung, Michelle L. Brinkmeier & Sally A. Camper

  3. Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, NY, USA

    Leonard Y. M. Cheung

  4. Laboratory of Applied Research of Neurosciences (LIAN-CONICET), FLENI Sede Escobar, Buenos Aires, Argentina

    Gonzalo T. Chirino Felker, Lucia N. Moro & Santiago Miriuka

Authors
  1. María Inés Pérez Millán
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonard Y. M. Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Florencia Mercogliano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Andrea Camilletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gonzalo T. Chirino Felker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lucia N. Moro
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Santiago Miriuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michelle L. Brinkmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sally A. Camper
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.A.C., M.I.P.M. and L.Y.M.C. researched data for the article, contributed substantially to the discussion of content, wrote the article, and reviewed and/or edited the manuscript before submission. M.L.B. researched data for the article and reviewed and/or edited the manuscript before submission. F.M. and M.A.C. researched data for the article and wrote the article. G.T.C.F., L.N.M. and S.M. researched data for the article.

Corresponding author

Correspondence to Sally A. Camper.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Hidetaka Suga, who co-reviewed with Ryusaku Matsumoto; Juan Pedro Martinez-Barbera; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pérez Millán, M.I., Cheung, L.Y.M., Mercogliano, F. et al. Pituitary stem cells: past, present and future perspectives. Nat Rev Endocrinol 20, 77–92 (2024). https://doi.org/10.1038/s41574-023-00922-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-023-00922-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing