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system (CNS) offers transformative opportunities for modeling neurodegenerative diseases in vivo. This study evaluated the survival, integration, and functional properties of cryopreserved forebrain GABAergic neurons (iGABAs) derived from human induced pluripotent stem cells (iPSCs) across three species used in translational research. iGABAs were stereotactically injected into the striatum of Sprague\u2013Dawley rats, immunodeficient RNU rats, R6\/2 Huntington\u2019s disease (HD) mice, wild-type controls, and Cynomolgus monkeys. Post-transplantation, long-term assessments revealed robust neuronal survival, extensive neurite outgrowth, and integration with host CNS environments. In immunodeficient rats, iGABAs innervated the neuraxis, extending from the prefrontal cortex to the midbrain, while maintaining mature neuronal phenotypes without uncontrolled proliferation. Similarly, grafts in nonhuman primates showed localized survival and stable phenotype at one month. In the neurodegenerative milieu of HD mice, iGABAs survived up to six months, projecting into the host striatum and white matter, with evidence of mutant huntingtin aggregates localized within the graft, indicating pathological protein transfer. These findings underscore the utility of cryopreserved iGABAs as a reproducible, scalable model for disease-specific CNS investigations and mechanistic studies of proteinopathic propagation. This work establishes a critical platform for studying neurodegenerative diseases and developing therapeutic interventions.<\/jats:p>","DOI":"10.3390\/biology14020217","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T03:29:53Z","timestamp":1739935793000},"page":"217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Long-Term Engraftment of Cryopreserved Human Neurons for In Vivo Disease Modeling in Neurodegenerative Disease"],"prefix":"10.3390","volume":"14","author":[{"given":"David J.","family":"Marmion","sequence":"first","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Deng","sequence":"additional","affiliation":[{"name":"Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin M.","family":"Hiller","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel L.","family":"Lewis","sequence":"additional","affiliation":[{"name":"FujiFilm Cellular Dynamics Inc., Madison, WI 53711, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa J.","family":"Harms","sequence":"additional","affiliation":[{"name":"FujiFilm Cellular Dynamics Inc., Madison, WI 53711, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L.","family":"Cameron","sequence":"additional","affiliation":[{"name":"Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan A.","family":"Nolta","sequence":"additional","affiliation":[{"name":"Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey H.","family":"Kordower","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85281, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0235-5038","authenticated-orcid":false,"given":"Kyle D.","family":"Fink","sequence":"additional","affiliation":[{"name":"Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin R.","family":"Wakeman","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA"},{"name":"Department of Psychiatry, Yale University, New Haven, CT 06511, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.stem.2017.09.014","article-title":"Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson\u2019s Disease: Dawn of a New Era","volume":"21","author":"Barker","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1056\/NEJMoa1915872","article-title":"Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson\u2019s Disease","volume":"382","author":"Schweitzer","year":"2020","journal-title":"N. 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