{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T02:38:31Z","timestamp":1770345511744,"version":"3.49.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T00:00:00Z","timestamp":1668038400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K15917"],"award-info":[{"award-number":["JP20K15917"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K09838"],"award-info":[{"award-number":["JP20K09838"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP20bm0404036"],"award-info":[{"award-number":["JP20bm0404036"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP21ek0109524"],"award-info":[{"award-number":["JP21ek0109524"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The hypothalamus is comprised of heterogenous cell populations and includes highly complex neural circuits that regulate the autonomic nerve system. Its dysfunction therefore results in severe endocrine disorders. Although recent experiments have been conducted for <jats:italic>in vitro<\/jats:italic> organogenesis of hypothalamic neurons from embryonic stem (ES) or induced pluripotent stem (iPS) cells, whether these stem cell-derived hypothalamic neurons can be useful for regenerative medicine remains unclear. We therefore performed orthotopic transplantation of mouse ES cell (mESC)-derived hypothalamic neurons into adult mouse brains. We generated electrophysiologically functional hypothalamic neurons from mESCs and transplanted them into the supraoptic nucleus of mice. Grafts extended their axons along hypothalamic nerve bundles in host brain, and some of them even projected into the posterior pituitary (PPit), which consists of distal axons of the magnocellular neurons located in hypothalamic supraoptic and paraventricular nuclei. The axonal projections to the PPit were not observed when the mESC-derived hypothalamic neurons were ectopically transplanted into the substantia nigra reticular part. These findings suggest that our stem cell-based orthotopic transplantation approach might contribute to the establishment of regenerative medicine for hypothalamic and pituitary disorders.<\/jats:p>","DOI":"10.1371\/journal.pone.0276694","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T18:44:25Z","timestamp":1668105865000},"page":"e0276694","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Long-range axonal projections of transplanted mouse embryonic stem cell-derived hypothalamic neurons into adult mouse brain"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9243-8525","authenticated-orcid":true,"given":"Miho","family":"Kawata","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Kodani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahito","family":"Ohkuma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ei-ichi","family":"Miyachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoko S.","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Nakashima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1924-7639","authenticated-orcid":true,"given":"Hidetaka","family":"Suga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7348-7572","authenticated-orcid":true,"given":"Toshiki","family":"Kameyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kanako","family":"Saito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5997-2670","authenticated-orcid":true,"given":"Hiroshi","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,11,10]]},"reference":[{"key":"pone.0276694.ref001","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1177\/1073858417708284","article-title":"Oxytocin and Vasopressin: Powerful Regulators of Social Behavior","volume":"23","author":"HK Caldwell","year":"2017","journal-title":"Neuroscientist"},{"key":"pone.0276694.ref002","doi-asserted-by":"crossref","first-page":"6443","DOI":"10.1113\/JP271946","article-title":"Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour","volume":"594","author":"P Bonnavion","year":"2016","journal-title":"J Physiol"},{"key":"pone.0276694.ref003","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1038\/nn.3211","article-title":"Unraveling the brain regulation of appetite: Lessons from genetics","volume":"15","author":"GSH Yeo","year":"2012","journal-title":"Nat Neurosci"},{"key":"pone.0276694.ref004","doi-asserted-by":"crossref","first-page":"R1111","DOI":"10.1016\/j.cub.2014.10.023","article-title":"The hypothalamus","volume":"24","author":"CB Saper","year":"2014","journal-title":"Curr Biol"},{"key":"pone.0276694.ref005","first-page":"2","article-title":"Diabetes Insipidus: A Review","volume":"s6","author":"M Shapiro","year":"2012","journal-title":"J Diabetes Metab"},{"key":"pone.0276694.ref006","doi-asserted-by":"crossref","first-page":"11796","DOI":"10.1073\/pnas.0803078105","article-title":"Minimization of exogenous signals in ES cell culture induces rostral hypothalamic differentiation","volume":"105","author":"T Wataya","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0276694.ref007","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature10637","article-title":"Self-formation of functional adenohypophysis in three-dimensional culture","volume":"480","author":"H Suga","year":"2011","journal-title":"Nature"},{"key":"pone.0276694.ref008","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1016\/j.celrep.2013.10.048","article-title":"Specification of functional cranial placode derivatives from human pluripotent stem cells","volume":"5","author":"Z Dincer","year":"2013","journal-title":"Cell Rep"},{"key":"pone.0276694.ref009","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-22053-x","article-title":"Vasopressin-secreting neurons derived from human embryonic stem cells through specific induction of dorsal hypothalamic progenitors","volume":"8","author":"K Ogawa","year":"2018","journal-title":"Sci Rep"},{"key":"pone.0276694.ref010","doi-asserted-by":"crossref","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":"T Kasai","year":"2020","journal-title":"Cell Rep"},{"key":"pone.0276694.ref011","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1242\/dev.117978","article-title":"Generation of neuropeptidergic hypothalamic neurons from human pluripotent stem cells","volume":"142","author":"FT Merkle","year":"2015","journal-title":"Development"},{"key":"pone.0276694.ref012","first-page":"7","article-title":"Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells","author":"C Ozone","year":"2016","journal-title":"Nat Commun"},{"key":"pone.0276694.ref013","doi-asserted-by":"crossref","first-page":"858","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":"B Zimmer","year":"2016","journal-title":"Stem Cell Reports"},{"key":"pone.0276694.ref014","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/BF00656997","article-title":"Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches","volume":"391","author":"OP Hamill","year":"1981","journal-title":"Pflugers Arch"},{"key":"pone.0276694.ref015","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0896-6273(01)00299-9","article-title":"Na+ action potentials in human photoreceptors","volume":"30","author":"F Kawai","year":"2001","journal-title":"Neuron"},{"key":"pone.0276694.ref016","first-page":"317","article-title":"Patch-clamp Recording of Human Retinal Photoreceptors and Bipolar Cells","volume":"83","author":"M Ohkuma","year":"2007","journal-title":"Photochem Photobiol"},{"key":"pone.0276694.ref017","volume-title":"The Mouse Brain in Stereotaxic Coordinates","author":"G Paxinos","year":"2004","edition":"2"},{"key":"pone.0276694.ref018","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature05453","article-title":"Genome-wide atlas of gene expression in the adult mouse brain","volume":"445","author":"ES Lein","year":"2007","journal-title":"Nature"},{"key":"pone.0276694.ref019","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/j.stemcr.2020.06.016","article-title":"Axonal Extensions along Corticospinal Tracts from Transplanted Human Cerebral Organoids","volume":"15","author":"T Kitahara","year":"2020","journal-title":"Stem Cell Reports"},{"key":"pone.0276694.ref020","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1177\/0963689717744788","article-title":"The Effect of Tissue Preparation and Donor Age on Striatal Graft Morphology in the Mouse","volume":"27","author":"DJ Harrison","year":"2018","journal-title":"Cell Transplant"},{"key":"pone.0276694.ref021","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1620\/tjem.95.177","article-title":"Estimation of the cell Number of heart muscles in normal rats","volume":"95","author":"R Sasaki","year":"1968","journal-title":"Tohoku J Exp Med"},{"key":"pone.0276694.ref022","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/ar.1090940210","article-title":"Estimation of nuclear population from microtome sections","volume":"94","author":"M. Abercrombie","year":"1946","journal-title":"Anat Rec"},{"key":"pone.0276694.ref023","first-page":"225","article-title":"Regulation of Neuronal Activity in Hypothalamic Vasopressin Neurons","volume":"21","author":"T Ohbuchi","year":"2015","journal-title":"Interdiscip Inf Sci."},{"key":"pone.0276694.ref024","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fnins.2016.00109","article-title":"Electrophysiology of hypothalamic magnocellular neurons in vitro: A rhythmic drive in organotypic cultures and acute slices","volume":"10","author":"JM Israel","year":"2016","journal-title":"Front Neurosci."},{"key":"pone.0276694.ref025","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/cne.20741","article-title":"Patterns of axonal branching of neurons of the substantia nigra pars reticulata and pars lateralis in the rat","volume":"492","author":"C Cebri\u00e1n","year":"2005","journal-title":"J Comp Neurol"},{"key":"pone.0276694.ref026","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.neuron.2011.11.030","article-title":"Evoked axonal oxytocin release in the central amygdala attenuates fear response","volume":"73","author":"HS Knobloch","year":"2012","journal-title":"Neuron"},{"key":"pone.0276694.ref027","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fncir.2016.00092","article-title":"Hypothalamic vasopressinergic projections innervate central amygdala GABAergic neurons: Implications for anxiety and stress coping","volume":"10","author":"VS Hern\u00e1ndez","year":"2016","journal-title":"Front Neural Circuits"},{"key":"pone.0276694.ref028","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/S0006-8993(96)00873-6","article-title":"Pituitary gland receives both central and peripheral neuropeptide Y innervation","volume":"740","author":"S Vanhatalo","year":"1996","journal-title":"Brain Res"},{"key":"pone.0276694.ref029","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/0306-4522(82)90044-6","article-title":"Electrophysiology of hypothalamic magnocellular neurones secreting oxytocin and vasopressin","volume":"7","author":"DA Poulain","year":"1982","journal-title":"Neuroscience"},{"key":"pone.0276694.ref030","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0301-0082(95)80005-S","article-title":"Morphological and electrophysiological classification of hypothalamic supraoptic neurons","volume":"47","author":"WE Armstrong","year":"1995","journal-title":"Prog Neurobiol"},{"key":"pone.0276694.ref031","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/j.1365-2826.2010.01979.x","article-title":"Electrophysiological identification of the functional presynaptic nerve terminals on an isolated single vasopressin neurone of the rat supraoptic nucleus","volume":"22","author":"T Ohbuchi","year":"2010","journal-title":"J Neuroendocrinol"},{"key":"pone.0276694.ref032","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1016\/j.stem.2018.03.009","article-title":"Super-Obese Patient-Derived iPSC Hypothalamic Neurons Exhibit Obesogenic Signatures and Hormone Responses","volume":"22","author":"U Rajamani","year":"2018","journal-title":"Cell Stem Cell"},{"key":"pone.0276694.ref033","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1172\/JCI79220","article-title":"Differentiation of hypothalamic-like neurons from human pluripotent stem cells","volume":"125","author":"L Wang","year":"2015","journal-title":"J Clin Invest"},{"key":"pone.0276694.ref034","first-page":"1","article-title":"Stem cell transplantation therapy in Parkinson\u2019s disease","volume":"4","author":"MH Fu","year":"2015","journal-title":"Springerplus"},{"key":"pone.0276694.ref035","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1006\/exnr.2000.7476","article-title":"Time course of apoptotic cell death within mesencephalic cell suspension grafts: Implications for improving grafted dopamine neuron survival","volume":"165","author":"CE Sortwell","year":"2000","journal-title":"Exp Neurol"},{"key":"pone.0276694.ref036","first-page":"11","article-title":"Long-Term Evaluation of Intranigral Transplantation of Human iPSC-Derived Dopamine Neurons in a Parkinson\u2019s Disease Mouse Model","author":"S Brot","year":"2022","journal-title":"Cells"},{"key":"pone.0276694.ref037","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.neuron.2015.02.001","article-title":"Area-specific reestablishment of damaged circuits in the adult cerebral cortex by cortical neurons derived from mouse embryonic stem cells","volume":"85","author":"KA Michelsen","year":"2015","journal-title":"Neuron"},{"key":"pone.0276694.ref038","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1016\/j.celrep.2018.04.094","article-title":"Human Pluripotent Stem-Cell-Derived Cortical Neurons Integrate Functionally into the Lesioned Adult Murine Visual Cortex in an Area-Specific Way","volume":"23","author":"I Espuny-Camacho","year":"2018","journal-title":"Cell Rep"},{"key":"pone.0276694.ref039","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1016\/j.celrep.2019.08.058","article-title":"hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson\u2019s Disease","volume":"28","author":"AF Adler","year":"2019","journal-title":"Cell Rep"},{"key":"pone.0276694.ref040","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.stem.2020.08.014","article-title":"Human Stem Cell-Derived Neurons Repair Circuits and Restore Neural Function","volume":"28","author":"M Xiong","year":"2021","journal-title":"Cell Stem Cell"},{"key":"pone.0276694.ref041","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s00018-011-0759-6","article-title":"Human embryonic stem cell-derived neurons establish region-specific, long-range projections in the adult brain","volume":"69","author":"JA Steinbeck","year":"2012","journal-title":"Cell Mol Life Sci"},{"key":"pone.0276694.ref042","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.neuron.2013.12.015","article-title":"Pioneering axons regulate neuronal polarization in the developing cerebral cortex","volume":"81","author":"T Namba","year":"2014","journal-title":"Neuron"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0276694","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T18:45:25Z","timestamp":1668105925000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0276694"}},"subtitle":[],"editor":[{"given":"Robert","family":"Blum","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2022,11,10]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0276694","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,10]]}}}