{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:57:35Z","timestamp":1790747855139,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100008903","name":"Ministry of Health and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008903","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Parkinson's disease (PD) involves progressive degeneration of nigrostriatal ventral midbrain dopaminergic (vmDA) neurons and Lewy body proteopathy, necessitating scalable, lineage\u2010faithful donor cells. However, variability in human pluripotent stem cell (hPSC) differentiation and incomplete ventral midbrain identity limit translational use. Here, we establish a developmentally guided differentiation protocol that reproducibly specifies EN1\u2010positive vmDA progenitors through temporally optimized SHH, WNT\/\u03b2\u2010catenin, and FGF8 signaling. The resulting progenitors mature into vmDA neurons exhibiting stimulus\u2010dependent dopamine release and maturation\u2010associated pacemaking activity. Progenitors can be cryopreserved at a defined stage while retaining viability and neurogenic capacity. Functional validation was performed using complementary proteopathy\u2010based PD models. In vitro, optogenetic induction of \u03b1\u2010synuclein aggregation (\n                    <jats:italic>OASIS<\/jats:italic>\n                    ) triggered robust aggregate formation and selective degeneration of TH\u2010positive vmDA neurons in both two\u2010dimensional cultures and three\u2010dimensional neurospheroids. In vivo, we established a conditional \u03b223 proteopathy\u2010based PD mouse model exhibiting progressive nigrostriatal degeneration and motor impairment. Transplantation of hESC\u2010derived vmDA progenitors into advanced\u2010stage PD mice led to graft survival, differentiation into vmDA neurons, and significant motor improvement. Together, these findings define a robust vmDA differentiation framework validated across proteopathy\u2010based disease modeling and transplantation contexts, supporting its application in PD modeling and cell therapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.78007","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:14:56Z","timestamp":1790745296000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Developmentally Guided Differentiation of Ventral Midbrain Dopaminergic Cells Validated in Proteopathy\u2010Based Parkinson's Disease Models"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5611-888X","authenticated-orcid":false,"given":"Heechang","family":"Moon","sequence":"first","affiliation":[{"name":"Department of Biomedical Science Graduate School of Biomedical Science and Engineering Hanyang University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9801-5088","authenticated-orcid":false,"given":"Heejeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine  Suwon Republic of Korea"},{"name":"Bio Healthcare Central Research Center Hyper Corporation Inc.  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0030-4656","authenticated-orcid":false,"given":"Elliot H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Brain Science Institute Korea Institute of Science and Technology  Seoul Republic of Korea"},{"name":"Department of Biotechnology College of Life Science and Biotechnology Yonsei University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3017-2910","authenticated-orcid":false,"given":"Hanseul","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science Graduate School of Biomedical Science and Engineering Hanyang University  Seoul Republic of Korea"},{"name":"Hanyang Institute of Bioscience and Biotechnology Hanyang University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8508-915X","authenticated-orcid":false,"given":"Ji Hun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine  Suwon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5005-4398","authenticated-orcid":false,"given":"Huisu","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science Graduate School of Biomedical Science and Engineering Hanyang University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwon","family":"Cheon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine  Suwon Republic of 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Korea"},{"name":"Department of Life Science College of Natural Sciences Hanyang University  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0900-7386","authenticated-orcid":false,"given":"Soo\u2010Jin","family":"Oh","sequence":"additional","affiliation":[{"name":"Brain Science Institute Korea Institute of Science and Technology  Seoul Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0182-2279","authenticated-orcid":false,"given":"Yunjong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Samsung Biomedical Research Institute Sungkyunkwan University School of Medicine  Suwon Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9249-8664","authenticated-orcid":false,"given":"Yohan","family":"Oh","sequence":"additional","affiliation":[{"name":"Department 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