{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T09:14:58Z","timestamp":1780391698272,"version":"3.54.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP13bm0404018, JP18bm0404036, JP21ek0109524"],"award-info":[{"award-number":["JP13bm0404018, JP18bm0404036, JP21ek0109524"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K08859, JP20K08896, JP20K11658, JP20K15917"],"award-info":[{"award-number":["JP20K08859, JP20K08896, JP20K11658, JP20K15917"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"publisher","award":["JPMJFR200N"],"award-info":[{"award-number":["JPMJFR200N"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Human stem cell-derived organoid culture enables the <jats:italic>in vitro<\/jats:italic> analysis of the cellular function in three-dimensional aggregates mimicking native organs, and also provides a valuable source of specific cell types in the human body. We previously established organoid models of the hypothalamic-pituitary (HP) complex using human pluripotent stem cells. Although the models are suitable for investigating developmental and functional HP interactions, we consider that isolated pituitary cells are also useful for basic and translational research on the pituitary gland, such as stem cell biology and regenerative medicine. To develop a method for the purification of pituitary cells in HP organoids, we performed surface marker profiling of organoid cells derived from human induced pluripotent stem cells (iPSCs). Screening of 332 human cell surface markers and a subsequent immunohistochemical analysis identified epithelial cell adhesion molecule (EpCAM) as a surface marker of anterior pituitary cells, as well as their ectodermal precursors. EpCAM was not expressed on hypothalamic lineages; thus, anterior pituitary cells were successfully enriched by magnetic separation of EpCAM<jats:sup>+<\/jats:sup> cells from iPSC-derived HP organoids. The enriched pituitary population contained functional corticotrophs and their progenitors; the former responded normally to a corticotropin-releasing hormone stimulus. Our findings would extend the applicability of organoid culture as a novel source of human anterior pituitary cells, including stem\/progenitor cells and their endocrine descendants.<\/jats:p>","DOI":"10.3389\/fendo.2022.941166","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T12:23:08Z","timestamp":1657628588000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["EpCAM Is a Surface Marker for Enriching Anterior Pituitary Cells From Human Hypothalamic-Pituitary Organoids"],"prefix":"10.3389","volume":"13","author":[{"given":"Yu","family":"Kodani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miho","family":"Kawata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Suga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takatoshi","family":"Kasai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikafumi","family":"Ozone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Sakakibara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kuwahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Taga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Arima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiki","family":"Kameyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanako","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1210\/er.2009-0008","article-title":"Genetic Regulation of Pituitary Gland Development in Human and Mouse","volume":"30","author":"Kelberman","year":"2009","journal-title":"Endocr Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10351","article-title":"Functional Anterior Pituitary Generated in Self-Organizing Culture of Human Embryonic Stem Cells","volume":"7","author":"Ozone","year":"2016","journal-title":"Nat Commun"},{"key":"B3","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.celrep.2019.12.009","article-title":"Hypothalamic Contribution to Pituitary Functions is Recapitulated In Vitro Using 3D-Cultured Human iPS Cells","volume":"30","author":"Kasai","year":"2020","journal-title":"Cell Rep"},{"key":"B4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature10637","article-title":"Self-Formation of Functional Adenohypophysis in Three-Dimensional Culture","volume":"480","author":"Suga","year":"2011","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI127378","article-title":"Congenital Pituitary Hypoplasia Model Demonstrates Hypothalamic OTX2 Regulation of Pituitary Progenitor Cells","volume":"130","author":"Matsumoto","year":"2020","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.604519","article-title":"Pituitary Remodeling Throughout Life: Are Resident Stem Cells Involved","volume":"11","author":"Laporte","year":"2021","journal-title":"Front Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2005.04.023","article-title":"Identification and Enrichment of Colony-Forming Cells From the Adult Murine Pituitary","volume":"308","author":"Lepore","year":"2005","journal-title":"Exp Cell Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0185","article-title":"The Adult Pituitary Contains a Cell Population Displaying Stem\/Progenitor Cell and Early Embryonic Characteristics","volume":"146","author":"Chen","year":"2005","journal-title":"Endocrinology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0801644105","article-title":"Genetic Approaches Identify Adult Pituitary Stem Cells","volume":"105","author":"Gleiberman","year":"2008","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/stem.51","article-title":"Pituitary Progenitor Cells Tracked Down by Side Population Dissection","volume":"27","author":"Chen","year":"2009","journal-title":"Stem Cells"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e4815","DOI":"10.1371\/journal.pone.0004815","article-title":"A GRFa2\/Prop1\/stem (GPS) Cell Niche in the Pituitary","volume":"4","author":"Garcia-Lavandeira","year":"2009","journal-title":"PloS One"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.5414\/npp28309","article-title":"Evidence for a Progenitor Cell Population in the Human Pituitary","volume":"28","author":"Weiss","year":"2009","journal-title":"Clin Neuropathol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-012-0957-9","article-title":"Identification of Novel Pathways Involved in the Pathogenesis of Human Adamantinomatous Craniopharyngioma","volume":"124","author":"Andoniadou","year":"2012","journal-title":"Acta Neuropathol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.07.004","article-title":"Sox2(+) Stem\/Progenitor Cells in the Adult Mouse Pituitary Support Organ Homeostasis and Have Tumor-Inducing Potential","volume":"13","author":"Andoniadou","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2013.07.006","article-title":"Mobilized Adult Pituitary Stem Cells Contribute to Endocrine Regeneration in Response to Physiological Demand","volume":"13","author":"Rizzoti","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2016.08.016","article-title":"Isolation of Adult Pituitary Stem\/Progenitor Cell Clusters Located in the Parenchyma of the Rat Anterior Lobe","volume":"17","author":"Yoshida","year":"2016","journal-title":"Stem Cell Res"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5533","DOI":"10.1038\/s41598-018-23923-0","article-title":"Isolation and Characterisation of CD9-Positive Pituitary Adult Stem\/Progenitor Cells in Rats","volume":"8","author":"Horiguchi","year":"2018","journal-title":"Sci Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1530\/JOE-18-0462","article-title":"Organoids From Pituitary as a Novel Research Model Toward Pituitary Stem Cell Exploration","volume":"240","author":"Cox","year":"2019","journal-title":"J Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2021.102223","article-title":"Isolation of PRRX1-Positive Adult Pituitary Stem\/Progenitor Cells From the Marginal Cell Layer of the Mouse Anterior Lobe","volume":"52","author":"Shintani","year":"2021","journal-title":"Stem Cell Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.15698\/cst2019.06.188","article-title":"Biology and Clinical Relevance of EpCAM","volume":"3","author":"Keller","year":"2019","journal-title":"Cell Stress Chaperones"},{"key":"B21","article-title":"Immunohistochemical Study of the Expression of a Mr 34,000 Human Epithelium-Specific Surface Glycoprotein in Normal and Malignant Tissues","volume":"47","author":"Momburg","year":"1987","journal-title":"Cancer Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.anndiagpath.2010.06.008","article-title":"Epithelial Cell Adhesion Molecule Expression in Pituitary Adenomas: An Immunohistochemical Study","volume":"14","author":"Ortiz-Plata","year":"2010","journal-title":"Ann Diagn Pathol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/srep29731","article-title":"EpCAM (CD326) is Differentially Expressed in Craniopharyngioma Subtypes and Rathke\u2019s Cleft Cysts","volume":"6","author":"Thimsen","year":"2016","journal-title":"Sci Rep"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707886105","article-title":"SOX2-Expressing Progenitor Cells Generate All of the Major Cell Types in the Adult Mouse Pituitary Gland","volume":"105","author":"Fauquier","year":"2008","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.05.027","article-title":"PROP1 Coexists With SOX2 and Induces PIT1-Commitment Cells","volume":"385","author":"Yoshida","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2011.09.001","article-title":"Sox2(+) Adult Stem and Progenitor Cells are Important for Tissue Regeneration and Survival of Mice","volume":"9","author":"Arnold","year":"2011","journal-title":"Cell Stem Cell"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00623","article-title":"Cell Type- and Sex-Dependent Transcriptome Profiles of Rat Anterior Pituitary Cells","volume":"10","author":"Fletcher","year":"2019","journal-title":"Front Endocrinol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.05.005","article-title":"Derivation of Diverse Hormone-Releasing Pituitary Cells From Human Pluripotent Stem Cells","volume":"6","author":"Zimmer","year":"2016","journal-title":"Stem Cell Rep"},{"key":"B30","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1530\/JOE-17-0258","article-title":"Stem\/progenitor Cells in Pituitary Organ Homeostasis and Tumourigenesis","volume":"236","author":"Haston","year":"2018","journal-title":"J Endocrinol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1159\/000488393","article-title":"Basic Research Advances on Pituitary Stem Cell Function and Regulation","volume":"107","author":"Russell","year":"2018","journal-title":"Neuroendocrinology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2011.02198.x","article-title":"Significant Quantitative and Qualitative Transition in Pituitary Stem \/ Progenitor Cells Occurs During the Postnatal Development of the Rat Anterior Pituitary","volume":"23","author":"Yoshida","year":"2011","journal-title":"J Neuroendocrinol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2187","article-title":"Craniopharyngiomas Express Embryonic Stem Cell Markers (SOX2, OCT4, KLF4, and SOX9) as Pituitary Stem Cells But do Not Coexpress RET\/GFRA3 Receptors","volume":"97","author":"Garcia-Lavandeira","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-020-09634-1","article-title":"Stem Cell Transcription Factor Sox2 is Expressed in a Subset of Folliculo-Stellate Cells of Growth Hormone-Producing Pituitary Neuroendocrine Tumours and its Expression Shows No Association With Tumour Size or IGF1 Levels: A Clinicopathological Study of 109 Cases","volume":"31","author":"Soukup","year":"2020","journal-title":"Endocr Pathol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2826.2008.01779.x","article-title":"Bovine Anterior Pituitary Progenitor Cell Line Expresses Interleukin (IL)-18 and IL-18 Receptor","volume":"20","author":"Nagai","year":"2008","journal-title":"J Neuroendocrinol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.21-0091","article-title":"Localization of Putative Pituitary Stem\/Progenitor Cells in Female Dairy Cattle","volume":"83","author":"Oguchi","year":"2021","journal-title":"J Vet Med Sci"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-020-19012-4","article-title":"Single-Cell Transcriptomics Identifies Divergent Developmental Lineage Trajectories During Human Pituitary Development","volume":"11","author":"Zhang","year":"2020","journal-title":"Nat Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-1890-0","article-title":"GFP-Expressing S100\u03b2-Positive Cells of the Rat Anterior Pituitary Differentiate Into Hormone-Producing Cells","volume":"357","author":"Higuchi","year":"2014","journal-title":"Cell Tissue Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1007\/s00418-020-01943-0","article-title":"Cluster of Differentiation (CD) 9-Positive Mouse Pituitary Cells are Adult Stem\/Progenitor Cells","volume":"155","author":"Horiguchi","year":"2021","journal-title":"Histochem Cell Biol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.941166\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T12:23:11Z","timestamp":1657628591000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2022.941166\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,12]]},"references-count":39,"alternative-id":["10.3389\/fendo.2022.941166"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2022.941166","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,12]]},"article-number":"941166"}}