Application of pluripotent stem cells for treatment of human neuroendocrine disorders
The neuroendocrine system is composed of many types of functional cells. Matured cells are generally irreversible to progenitor cells and it is difficult to obtain enough from our body. Therefore, studying specific subtypes of human neuroendocrine cells in vitro has not been feasible. One of the solutions is pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. These are unlimited sources and, in theory, are able to give rise to all cell types of our body. Therefore, we can use them for regenerative medicine, developmental basic research and disease modeling. Based on this idea, differentiation methods have been studied for years. Recent studies have successfully induced hypothalamic-like progenitors from mouse and human ES/iPS cells. The induced hypothalamic-like progenitors generated hypothalamic neurons, for instance, vasopressin neurons. Induction to adenohypophysis was also reported in the manner of self-formation by three-dimensional floating cultures. Rathke’s pouch-like structures, i.e., pituitary anlage, were self-organized in accordance with pituitary development in embryo. Pituitary hormone-producing cells were subsequently differentiated. The induced corticotrophs secreted adrenocorticotropic hormone in response to corticotropin-releasing hormone. When engrafted in vivo, these cells rescued systemic glucocorticoid levels in hypopituitary mice. These culture methods were characterized by replication of stepwise embryonic differentiation. It is based on the idea of mimicking the molecular environment of embryogenesis. Thanks to these improvements, these days, we can generate hormone-secreting neuroendocrine cells from pluripotent stem cells. The next problems that need to be solved are improving differentiation efficiency even further and structuring networks.
KeywordsHypothalamus Pituitary Embryonic stem cells Differentiation
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Garcia-Lavandeira M, Saez C, Diaz-Rodriguez E, Perez-Romero S, Senra A, Dieguez C, Japon MA, Alvarez CV (2012) Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors. J Clin Endocrinol Metab 97:E80–E87CrossRefGoogle Scholar
- Gaston-Massuet C, Andoniadou CL, Signore M, Jayakody SA, Charolidi N, Kyeyune R, Vernay B, Jacques TS, Taketo MM, Le Tissier P, Dattani MT, Martinez-Barbera JP (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci U S A 108:11482–11487CrossRefGoogle Scholar
- Hahner S, Spinnler C, Fassnacht M, Burger-Stritt S, Lang K, Milovanovic D, Beuschlein F, Willenberg HS, Quinkler M, Allolio B (2015) High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab 100:407–416CrossRefGoogle Scholar
- Kawasaki H, Suemori H, Mizuseki K, Watanabe K, Urano F, Ichinose H, Haruta M, Takahashi M, Yoshikawa K, Nishikawa S, Nakatsuji N, Sasai Y (2002) Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci U S A 99:1580–1585CrossRefGoogle Scholar
- Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, Vankelecom H, Kineman RD (2011) Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One 6:e15767. https://doi.org/10.1371/journal.pone.0015767 CrossRefGoogle Scholar
- Ogawa K, Suga H, Ozone C, Sakakibara M, Yamada T, Kano M, Mitsumoto K, Kasai T, Kodani Y, Nagasaki H, Yamamoto N, Hagiwara D, Goto M, Banno R, Sugimura Y, Arima H (2018) Vasopressin-secreting neurons derived from human embryonic stem cells through specific induction of dorsal hypothalamic progenitors. Sci Rep 8:3615. https://doi.org/10.1038/s41598-018-22053-x CrossRefGoogle Scholar
- Sakaguchi H, Kadoshima T, Soen M, Narii N, Ishida Y, Ohgushi M, Takahashi J, Eiraku M, Sasai Y (2015) Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun 6:8896. https://doi.org/10.1038/ncomms9896 CrossRefGoogle Scholar
- Sherlock M, Reulen RC, Alonso AA, Ayuk J, Clayton RN, Sheppard MC, Hawkins MM, Bates AS, Stewart PM (2009) ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly. J Clin Endocrinol Metab 94:4216–4223CrossRefGoogle Scholar
- Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O'Connell SM, Gukovsky I, Carrière C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Andersen B, Beamer WG, Rosenfeld MG (1996) Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 384:327–333CrossRefGoogle Scholar
- Takuma N, Sheng HZ, Furuta Y, Ward JM, Sharma K, Hogan BL, Pfaff SL, Westphal H, Kimura S, Mahon KA (1998) Formation of Rathke’s pouch requires dual induction from the diencephalon. Development 125:4835–4840Google Scholar