{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:32:44Z","timestamp":1790767964477,"version":"4.1.0"},"reference-count":72,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"NIH","award":["NINDS R35NS122302"],"award-info":[{"award-number":["NINDS R35NS122302"]}]},{"name":"NIH","award":["T32-GM007315"],"award-info":[{"award-number":["T32-GM007315"]}]},{"name":"NIH","award":["T32GM007863"],"award-info":[{"award-number":["T32GM007863"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Huntington's Disease"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:p>Two- and three-dimensional (2D and 3D) cell models derived from human stem cells have shed light on a wide range of molecular and cellular features of Huntington's disease (HD). Here we review the use of human stem cell-derived models to explore neurodevelopmental contributions to HD. We provide a timeline of key advances made in 2D and 3D model systems, ranging from differentiated monocultures to brain-like organoids and assembloids. Models along this spectrum have advanced our understanding of various disease-associated characteristics including disease protein (huntingtin) aggregation, somatic repeat instability, transcriptional dysregulation, perturbations in neurodevelopmental staging, and neural circuitry. We highlight recent findings in brain-like organoids which, despite being a relatively recent innovation, are proving to be a promising tool with which to study aberrant neurodevelopmental features of HD. All models have their limitations, and we compare and contrast the utility and limitations of various stem cell-based methods to study HD. Finally, we speculate on future advances employing advanced computational and transcriptomic methods that will expand the power of 3D model systems for the study of HD and related neurodegenerative disorders.<\/jats:p>","DOI":"10.1177\/18796397251399701","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T15:23:02Z","timestamp":1765552982000},"page":"214-225","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":2,"title":["Insights into neurodevelopmental features of Huntington's disease from stem cell-derived models including organoids"],"prefix":"10.1177","volume":"15","author":[{"given":"Mariana","family":"Sierra","sequence":"first","affiliation":[{"name":"University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6425-1341","authenticated-orcid":false,"given":"Rachael","family":"Powers","sequence":"additional","affiliation":[{"name":"University of Michigan"},{"name":"University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2437-6451","authenticated-orcid":false,"given":"Nikolas","family":"Grotewold","sequence":"additional","affiliation":[{"name":"University of Michigan"},{"name":"University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0382-7535","authenticated-orcid":false,"given":"Henry","family":"Paulson","sequence":"additional","affiliation":[{"name":"University of Michigan"},{"name":"University of Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nicl.2020.102211"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(10)70276-3"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad275"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1385\/MN:28:3:259"},{"key":"e_1_3_2_6_2","first-page":"65","article-title":"The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology","volume":"5","author":"Schulte J","year":"2011","unstructured":"Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington's Disease pathology. Curr Trends Neurol 2011; 5: 65\u201378.","journal-title":"Curr Trends Neurol"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57552"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax3338"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000838"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50877-x"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awq280"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009364"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-021-02269-4"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.04.027"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy375"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0237-5"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51216-w"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2316176121"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1066"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0503634102"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.12.013"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1135"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13649"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.05.025"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05320-3"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1472-6483(10)60053-3"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-219220"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx327"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-016-0092-5"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36096-w"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0075-7"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2012.04.026"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.166074"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-024-02562-0"},{"key":"e_1_3_2_35_2","article-title":"Identification of neurodevelopmental organization of the cell populations of juvenile Huntington\u2019s disease using dorso-ventral HD organoids and HD mouse embryos","volume":"14","author":"\u015awito\u0144ska-Kurkowska K","year":"2025","unstructured":"\u015awito\u0144ska-Kurkowska K, Kubi\u015b J, Delimata-Raczek J, et al. Identification of neurodevelopmental organization of the cell populations of juvenile Huntington\u2019s disease using dorso-ventral HD organoids and HD mouse embryos. Elife 2025; 14: RP102879.","journal-title":"Elife"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2018.11"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2020.08.005"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02183-1"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-200414"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq456"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.02.008"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2011.12.042"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adn4600"},{"key":"e_1_3_2_44_2","first-page":"850586","article-title":"Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids","author":"Zhang J","year":"2019","unstructured":"Zhang J, Ooi J, Utami KH, et al. Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids. bioRxiv 2019: 850586.","journal-title":"bioRxiv"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.09.076"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/stem.3420"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2015.11.005"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0715-14.2014"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1371\/annotation\/edee8dfa-6b2a-44f4-866a-098f186e27f0"},{"key":"e_1_3_2_50_2","article-title":"Selective roles of normal and mutant huntingtin in neural induction and early neurogenesis","volume":"8","author":"Nguyen GD","year":"2013","unstructured":"Nguyen GD, Gokhan S, Molero AE, et al. Selective roles of normal and mutant huntingtin in neural induction and early neurogenesis. PLoS One 2013; 8: e64368.","journal-title":"PLoS One"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1715865115"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105140"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.2595"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2007-1041"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/cercor\/bhs252"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.02.002"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap8809"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202215851"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1529"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12517"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3415"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2022.100297"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-48343-7"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2025.05.014"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50626-0"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-35752-x"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-024-01871-3"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.109397"},{"key":"e_1_3_2_69_2","article-title":"Application of spatial transcriptomics across organoids: a high-resolution spatial whole-transcriptome benchmarking dataset","author":"Nucera NCMR","year":"2025","unstructured":"Nucera NCMR, Leung RF, Leichter A, et al. Application of spatial transcriptomics across organoids: a high-resolution spatial whole-transcriptome benchmarking dataset. bioRxiv 2025.","journal-title":"bioRxiv"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.crmeth.2023.100573"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41928-023-01069-w"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-025-08632-5"},{"key":"e_1_3_2_73_2","doi-asserted-by":"crossref","unstructured":"Corey Rountree ES Coungeris N Alstat V et al. Long-term potentiation and closed-loop learning in paired brain organoids for cns drug discovery. 2025.","DOI":"10.1101\/2025.07.03.663054"}],"container-title":["Journal of Huntington's Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/18796397251399701","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/18796397251399701","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/18796397251399701","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T13:48:08Z","timestamp":1779889688000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/18796397251399701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":72,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["10.1177\/18796397251399701"],"URL":"https:\/\/doi.org\/10.1177\/18796397251399701","relation":{},"ISSN":["1879-6397","1879-6400"],"issn-type":[{"value":"1879-6397","type":"print"},{"value":"1879-6400","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]}}}