{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:06:00Z","timestamp":1792782360483,"version":"4.5.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2021,11,11]],"date-time":"2021-11-11T00:00:00Z","timestamp":1636588800000},"content-version":"vor","delay-in-days":554,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T00:00:00Z","timestamp":1588723200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017M3A9B4061407"],"award-info":[{"award-number":["NRF-2017M3A9B4061407"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"iPS Bio, Inc"},{"name":"ReNeuron, United Kingdom"},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF\u20102017M3A9B4061407"],"award-info":[{"award-number":["NRF\u20102017M3A9B4061407"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington's disease (HD) is a devastating, autosomal-dominant neurodegenerative disease, for which there are currently no disease-modifying therapies. Clinical trials to replace the damaged striatal medium spiny neurons (MSNs) have been attempted in the past two decades but have met with only limited success. In this study, we investigated whether a clonal, conditionally immortalized neural stem cell line (CTX0E03), which has already shown safety and signals of efficacy in chronic ischemic stroke patients, could rescue deficits seen in an animal model of HD. After CTX0E03 transplantation into the quinolinic acid-lesioned rat model of HD, behavioral changes were measured using the rotarod, stepping, and staircase tests. In vivo differentiation and neuronal connections of the transplanted CTX0E03 cells were evaluated with immunohistochemical staining and retrograde tracing with Fluoro-Gold. We found that transplantation of CTX0E03 gave rise to a significant behavioral improvement compared with the sham- or fibroblast-transplanted group. Transplanted CTX0E03 formed MSNs (DARPP-32) and GABAergic neurons (GABA, GAD65\/67) with BDNF expression in the striatum, while cortically transplanted cells formed Tbr1-positive neurons. Using a retrograde label, we also found stable engraftment and connection of the transplanted cells with host brain tissues. CTX0E03 transplantation also reduced glial scar formation and inflammation, as well as increasing endogenous neurogenesis and angiogenesis. Overall, our results demonstrate that CTX0E03, a clinical-grade neural stem cell line, is effective for preclinical test in HD, and, therefore, will be useful for clinical development in the treatment of HD patients.<\/jats:p>\n                  <jats:sec>\n                    <jats:title\/>\n                  <\/jats:sec>","DOI":"10.1002\/stem.3191","type":"journal-article","created":{"date-parts":[[2020,5,6]],"date-time":"2020-05-06T06:06:13Z","timestamp":1588745173000},"page":"936-947","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Implantation of the clinical-grade human neural stem cell line,\n                    <i>CTX0E03<\/i>\n                    , rescues the behavioral and pathological deficits in the quinolinic acid-lesioned rodent model of Huntington's disease"],"prefix":"10.1093","volume":"38","author":[{"given":"Yongwoo","family":"Yoon","sequence":"first","affiliation":[{"name":"1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Sook","family":"Kim","sequence":"additional","affiliation":[{"name":"2 Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iksoo","family":"Jeon","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Eun","family":"Noh","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Jung","family":"Park","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suji","family":"Lee","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Hyun","family":"Park","sequence":"additional","affiliation":[{"name":"3 Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Stevanato","sequence":"additional","affiliation":[{"name":"4 ReNeuron, Pencoed Business Park, Bridgend, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Hicks","sequence":"additional","affiliation":[{"name":"4 ReNeuron, Pencoed Business Park, Bridgend, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randolph","family":"Corteling","sequence":"additional","affiliation":[{"name":"4 ReNeuron, Pencoed Business Park, Bridgend, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger A.","family":"Barker","sequence":"additional","affiliation":[{"name":"5 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Sinden","sequence":"additional","affiliation":[{"name":"4 ReNeuron, Pencoed Business Park, Bridgend, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6597-8208","authenticated-orcid":false,"given":"Jihwan","family":"Song","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea"},{"name":"6 iPS Bio, Inc., Seongnam-si, Gyeonggi-do, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,5,6]]},"reference":[{"key":"2022022510431600700_stem3191-bib-0001","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1002\/mds.25075","article-title":"The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis","volume":"27","author":"Pringsheim","year":"2012","journal-title":"Mov Disord"},{"key":"2022022510431600700_stem3191-bib-0002","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1002\/stem.2747","article-title":"Concise review: the use of stem cells for understanding and treating Huntington's disease","volume":"36","author":"Connor","year":"2018","journal-title":"Stem Cells"},{"key":"2022022510431600700_stem3191-bib-0003","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1602\/neurorx.1.4.394","article-title":"Cell therapy in Huntington's disease","volume":"1","author":"Dunnett","year":"2004","journal-title":"NeuroRx"},{"key":"2022022510431600700_stem3191-bib-0004","first-page":"77","volume-title":"Progress in Stem Cell Transplantation","author":"Kim","year":"2015"},{"key":"2022022510431600700_stem3191-bib-0005","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.neures.2005.03.016","article-title":"Intravenous administration of human neural stem cells induces functional recovery in Huntington's disease rat model","volume":"52","author":"Lee","year":"2005","journal-title":"Neurosci Res"},{"key":"2022022510431600700_stem3191-bib-0006","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.nbd.2004.01.016","article-title":"Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease","volume":"16","author":"Ryu","year":"2004","journal-title":"Neurobiol Dis"},{"key":"2022022510431600700_stem3191-bib-0007","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1007\/s00221-006-0689-y","article-title":"Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington's disease","volume":"177","author":"Johann","year":"2007","journal-title":"Exp Brain Res"},{"key":"2022022510431600700_stem3191-bib-0008","doi-asserted-by":"crossref","first-page":"628","DOI":"10.3389\/fnins.2017.00628","article-title":"Induced pluripotent stem cell-derived neural stem cell transplantations reduced behavioral deficits and ameliorated neuropathological changes in YAC128 mouse model of Huntington's disease","volume":"11","author":"Al-Gharaibeh","year":"2017","journal-title":"Front Neurosci"},{"key":"2022022510431600700_stem3191-bib-0009","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1177\/1545968309335978","article-title":"The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dose-dependent fashion","volume":"23","author":"Stroemer","year":"2009","journal-title":"Neurorehabil Neural Repair"},{"key":"2022022510431600700_stem3191-bib-0010","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/S0140-6736(16)30513-X","article-title":"Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study","volume":"388","author":"Kalladka","year":"2016","journal-title":"Lancet"},{"key":"2022022510431600700_stem3191-bib-0011","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.3727\/096368912X657936","article-title":"In vivo and in vitro characterization of the angiogenic effect of CTX0E03 human neural stem cells","volume":"22","author":"Hicks","year":"2013","journal-title":"Cell Transplant"},{"key":"2022022510431600700_stem3191-bib-0012","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1089\/scd.2017.0009","article-title":"Human neural stem cell therapy for chronic ischemic stroke: charting Progress from laboratory to patients","volume":"26","author":"Sinden","year":"2017","journal-title":"Stem Cells Dev"},{"key":"2022022510431600700_stem3191-bib-0013","first-page":"209","article-title":"Generating Excitotoxic lesion models of Huntington's disease","volume":"2018","author":"Lelos","year":"1780","journal-title":"Methods Mol Biol"},{"key":"2022022510431600700_stem3191-bib-0014","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.expneurol.2005.12.011","article-title":"A conditionally immortal clonal stem cell line from human cortical neuroepithelium for the treatment of ischemic stroke","volume":"199","author":"Pollock","year":"2006","journal-title":"Exp Neurol"},{"key":"2022022510431600700_stem3191-bib-0015","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jneumeth.2009.11.021","article-title":"Neuroanatomical tracing combined with in situ hybridization: analysis of gene expression patterns within brain circuits of interest","volume":"194","author":"Conte-Perales","year":"2010","journal-title":"J Neurosci Methods"},{"key":"2022022510431600700_stem3191-bib-0016","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1038\/nprot.2006.224","article-title":"BrdU assay for neurogenesis in rodents","volume":"1","author":"Wojtowicz","year":"2006","journal-title":"Nat Protoc"},{"key":"2022022510431600700_stem3191-bib-0017","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1126\/science.1152092","article-title":"Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin","volume":"318","author":"Hanna","year":"2007","journal-title":"Science"},{"key":"2022022510431600700_stem3191-bib-0018","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1002\/stem.1135","article-title":"Neuronal properties, in vivo effects, and pathology of a Huntington's disease patient-derived induced pluripotent stem cells","volume":"30","author":"Jeon","year":"2012","journal-title":"Stem Cells"},{"key":"2022022510431600700_stem3191-bib-0019","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.3727\/096368912X657323","article-title":"Therapeutic effect of BDNF-overexpressing human neural stem cells (HB1. F3. BDNF) in a rodent model of middle cerebral artery occlusion","volume":"22","author":"Chang","year":"2013","journal-title":"Cell Transplant"},{"key":"2022022510431600700_stem3191-bib-0020","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"2022022510431600700_stem3191-bib-0021","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1126\/science.6849138","article-title":"Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain","volume":"219","author":"Schwarcz","year":"1983","journal-title":"Science"},{"key":"2022022510431600700_stem3191-bib-0022","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1523\/JNEUROSCI.11-06-01649.1991","article-title":"Chronic quinolinic acid lesions in rats closely resemble Huntington's disease","volume":"11","author":"Beal","year":"1991","journal-title":"J Neurosci"},{"key":"2022022510431600700_stem3191-bib-0023","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/0361-9230(94)90109-0","article-title":"Behavioral and electrophysiological correlates of the quinolinic acid rat model of Huntington's disease in rats","volume":"35","author":"Popoli","year":"1994","journal-title":"Brain Res Bull"},{"key":"2022022510431600700_stem3191-bib-0024","first-page":"1016","article-title":"Behavior characterization of a model of Huntington's disease in rats, induced by quinolinic acid","volume":"30","author":"Francis","year":"2000","journal-title":"Rev Neurol"},{"key":"2022022510431600700_stem3191-bib-0025","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0014-4886(89)90170-2","article-title":"The quinolinic acid model of Huntington's disease: locomotor abnormalities","volume":"105","author":"Sanberg","year":"1989","journal-title":"Exp Neurol"},{"key":"2022022510431600700_stem3191-bib-0026","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/cne.20176","article-title":"Human neural stem cell transplants improve motor function in a rat model of Huntington's disease","volume":"475","author":"McBride","year":"2004","journal-title":"J Comp Neurol"},{"key":"2022022510431600700_stem3191-bib-0027","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/brain\/awn025","article-title":"Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity","volume":"131","author":"Rosas","year":"2008","journal-title":"Brain"},{"key":"2022022510431600700_stem3191-bib-0028","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1093\/brain\/awq047","article-title":"Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington's disease","volume":"133","author":"Thu","year":"2010","journal-title":"Brain"},{"key":"2022022510431600700_stem3191-bib-0029","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1002\/stem.1024","article-title":"Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke","volume":"30","author":"Smith","year":"2012","journal-title":"Stem Cells"},{"key":"2022022510431600700_stem3191-bib-0030","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.it.2015.04.007","article-title":"The choreography of neuroinflammation in Huntington's disease","volume":"36","author":"Crotti","year":"2015","journal-title":"Trends Immunol"},{"key":"2022022510431600700_stem3191-bib-0031","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/imm.12233","article-title":"Inflammation in neurodegenerative diseases\u2014an update","volume":"142","author":"Amor","year":"2014","journal-title":"Immunology"},{"key":"2022022510431600700_stem3191-bib-0032","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/brain\/awn109","article-title":"Debris clearance by microglia: an essential link between degeneration and regeneration","volume":"132","author":"Neumann","year":"2009","journal-title":"Brain"},{"key":"2022022510431600700_stem3191-bib-0033","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0033090","article-title":"Engulfing astrocytes protect neurons from contact-induced apoptosis following injury","volume":"7","author":"Loov","year":"2012","journal-title":"PLoS One"},{"key":"2022022510431600700_stem3191-bib-0034","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms11758","article-title":"Human glia can both induce and rescue aspects of disease phenotype in Huntington disease","volume":"7","author":"Benraiss","year":"2016","journal-title":"Nat Commun"},{"key":"2022022510431600700_stem3191-bib-0035","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"2022022510431600700_stem3191-bib-0036","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1615\/CritRevImmunol.v32.i6.10","article-title":"M1 and M2 macrophages: oracles of health and disease","volume":"32","author":"Mills","year":"2012","journal-title":"Crit Rev Immunol"},{"key":"2022022510431600700_stem3191-bib-0037","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0050444","article-title":"Human neural progenitor cell engraftment increases neurogenesis and microglial recruitment in the brain of rats with stroke","volume":"7","author":"Hassani","year":"2012","journal-title":"PLoS One"},{"key":"2022022510431600700_stem3191-bib-0038","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.stemcr.2017.11.005","article-title":"Human neural stem cell transplantation rescues functional deficits in R6\/2 and Q140 Huntington's disease mice","volume":"10","author":"Reidling","year":"2018","journal-title":"Stem Cell Rep"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.3191","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.3191","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.3191","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/38\/8\/936\/42610200\/stmcls_38_8_936.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/38\/8\/936\/42610200\/stmcls_38_8_936.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T05:45:56Z","timestamp":1645767956000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/38\/8\/936\/6409358"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,6]]},"references-count":38,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,5,6]]},"published-print":{"date-parts":[[2020,8,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.3191","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,8,1]]},"published":{"date-parts":[[2020,5,6]]},"assertion":[{"value":"2019-05-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-04-01","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}