{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:33:47Z","timestamp":1790948027210,"version":"4.1.0"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"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","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The pituitary gland, regulating various hormones, is central in the endocrine system. As spontaneous recovery from hypopituitarism is rare, and exogenous-hormone substitution is clumsy, pituitary replacement <jats:italic>via<\/jats:italic> regenerative medicine, using pluripotent stem cells, is desirable. We have developed a differentiation method that in mice yields pituitary organoids (POs) derived from human embryonic stem cells (hESC). Efficacy of these POs, transplanted subcutaneously into hypopituitary mice, in reversing hypopituitarism was studied.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>hESC-derived POs were transplanted into inguinal subcutaneous white adipose tissue (ISWAT) and beneath dorsal skin, a relatively avascular region (AR), of hypophysectomized severe combined immunodeficient (SCID) mice. Pituitary function was evaluated thereafter for \u00be 6mo, assaying basal plasma ACTH and ACTH response to corticotropin-releasing hormone (CRH) stimulation. Histopathologic examination of organoids 150d after transplantation assessed engraftment. Some mice received an inhibitor of vascular endothelial growth factor (VEGF) to permit assessment of how angiogenesis contributed to subcutaneous engraftment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During follow-up, both basal and CRH-stimulated plasma ACTH levels were significantly higher in the ISWAT group (<jats:italic>p<\/jats:italic> &amp;lt; 0.001 \u2013 0.05 and 0.001 \u2013 0.005, respectively) than in a sham-operated group. ACTH secretion also was higher in the ISWAT group than in the AR group. Histopathologic study found ACTH-producing human pituitary-cell clusters in both groups of allografts, which had acquired a microvasculature. POs qPCR showed expression of angiogenetic factors. Plasma ACTH levels decreased with VEGF-inhibitor administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Subcutaneous transplantation of hESC-derived POs into hypopituitary SCID mice efficaciously renders recipients ACTH-sufficient.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1130465","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T06:35:12Z","timestamp":1677738912000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Subcutaneous transplantation of human embryonic stem cells-derived pituitary organoids"],"prefix":"10.3389","volume":"14","author":[{"given":"Hiroo","family":"Sasaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Suga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhito","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Nagata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuma","family":"Kondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachi","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Sakakibara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika","family":"Soen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsutomu","family":"Miwata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyoshi","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Ozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiori","family":"Taga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kuwahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tokushige","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Arima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Saito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(07)60673-4","article-title":"Hypopituitarism","volume":"369","author":"Schneider","year":"2007","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-3191","article-title":"High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study","volume":"100","author":"Hahner","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-00437-2","article-title":"Insights into non-classic and emerging causes of hypopituitarism","volume":"17","author":"Prodam","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1007\/s12020-013-0127-4","article-title":"Etiology of hypopituitarism in tertiary care institutions in Turkish population: analysis of 773 patients from pituitary study group database","volume":"47","author":"Tanriverdi","year":"2014","journal-title":"Endocrine"},{"key":"B5","doi-asserted-by":"publisher","first-page":"R151","DOI":"10.1530\/eje-17-0009","article-title":"MECHANISMS IN ENDOCRINOLOGY: Hypophysitis: diagnosis and treatment","volume":"179","author":"Joshi","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B6","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":"B7","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":"B8","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":"B9","article-title":"Method for producing cell mass including pituitary tissue, and cell mass thereof. JP Patent application WO2019103129A1","author":"Nakano","year":""},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2014.04.019","article-title":"Path to the clinic: assessment of iPSC-based cell therapies in vivo in a nonhuman primate model","volume":"7","author":"Hong","year":"2014","journal-title":"Cell Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2015.01.006","article-title":"Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition","volume":"4","author":"Nori","year":"2015","journal-title":"Stem Cell Rep"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2008.09.002","article-title":"Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals","volume":"3","author":"Eiraku","year":"2008","journal-title":"Cell Stem Cell"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/endo-74-2-301","article-title":"Transauricular hypophysectomy in rats and mice","volume":"74","author":"Falconi","year":"1964","journal-title":"Endocrinology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.60.481","article-title":"Effect of three types of mixed anesthetic agents alternate to ketamine in mice","volume":"60","author":"Kawai","year":"2011","journal-title":"Exp Anim"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000001970","article-title":"The optimization of the prevascularization procedures for improving subcutaneous islet engraftment","volume":"102","author":"Uematsu","year":"2018","journal-title":"Transplantation"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3211","article-title":"A prevascularized subcutaneous device-less site for islet and cellular transplantation","volume":"33","author":"Pepper","year":"2015","journal-title":"Nat Biotechnol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000002162","article-title":"A novel subcutaneous site of islet transplantation superior to the liver","volume":"102","author":"Yasunami","year":"2018","journal-title":"Transplantation"},{"key":"B18","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1038\/nature10144","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.10.5672","article-title":"Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2","volume":"95","author":"Ortega","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B20","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1385\/ep:16:1:067","article-title":"Angiopoietins are expressed in the normal rat pituitary gland","volume":"16","author":"Nag","year":"2005","journal-title":"Endocr Pathol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32299","article-title":"A strategy of vascular-targeted therapy for liver fibrosis","volume":"76","author":"Lin","year":"2022","journal-title":"Hepatology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1097\/tp.0000000000003400","article-title":"Mechanism of transplanted islet engraftment in visceral white adipose tissue","volume":"104","author":"Sakata","year":"2020","journal-title":"Transplantation"},{"key":"B23","volume-title":"Anatomy, skin (Integument), epidermis","author":"Yousef","year":"2022"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2021.100466","article-title":"Insulin expression and c-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device","volume":"2","author":"Shapiro","year":"2021","journal-title":"Cell Rep Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.10.003","article-title":"Implanted pluripotent stem-cell-derived pancreatic endoderm cells secrete glucose-responsive c-peptide in patients with type 1 diabetes","volume":"28","author":"Ramzy","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1056\/nejm198912283212605","article-title":"The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency","volume":"321","author":"Salomon","year":"1989","journal-title":"N Engl J Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.12.8954042","article-title":"Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism","volume":"81","author":"Katznelson","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"B28","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1016\/j.stem.2019.02.005","article-title":"Targeted disruption of HLA genes via CRISPR-Cas9 generates iPSCs with enhanced immune compatibility","volume":"24","author":"Xu","year":"2019","journal-title":"Cell Stem Cell"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1130465\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T06:35:18Z","timestamp":1677738918000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1130465\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":28,"alternative-id":["10.3389\/fendo.2023.1130465"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1130465","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,2]]},"article-number":"1130465"}}