biostudies-literatureLi HBLRD VAU.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeNINDS NIH HHSU.S. Department of Veterans AffairsNew York State Stem Cell Science4407-4418https://www.ebi.ac.uk/biostudies/studies/S-EPMC9684358biostudies-literatureUnknown27(11)The degeneration of nigral (A9) dopaminergic (DA) neurons causes motor symptoms in Parkinson's disease (PD). We use small-molecule compounds to direct the differentiation of human induced pluripotent stem cells (iPSCs) to A9 DA neurons that share many important properties with their in vivo counterparts. The method generates a large percentage of TH⁺ neurons that express appropriate A9 markers, such as GIRK2 and ALDH1A1, but mostly not the A10 marker CALBINDIN. Functionally, they exhibit autonomous pacemaking based on L-type voltage-dependent Ca²⁺ channels and show autoreceptor-dependent regulation of dopamine release. When transplanted in the striatum of 6-OHDA-lesioned athymic rats, the human A9 DA neurons manifest robust survival and axon outgrowth, and ameliorate motor deficits in the rat PD model. The ability to generate patient-specific A9 DA autonomous pacemakers will significantly improve PD research and facilitate the development of disease-modifying therapies.Molecular psychiatryGeneration of human A9 dopaminergic pacemakers from induced pluripotent stem cells.PMC9684358R56 NS102148I01 BX003831C30290GGR01 NS102148NS102148NS113763R01 NS113763BX003831Li HYan ZFeng JJiang HLi LfalseGeneration of human A9 dopaminergic pacemakers from induced pluripotent stem cells.The degeneration of nigral (A9) dopaminergic (DA) neurons causes motor symptoms in Parkinson's disease (PD). We use small-molecule compounds to direct the differentiation of human induced pluripotent stem cells (iPSCs) to A9 DA neurons that share many important properties with their in vivo counterparts. The method generates a large percentage of TH⁺ neurons that express appropriate A9 markers, such as GIRK2 and ALDH1A1, but mostly not the A10 marker CALBINDIN. Functionally, they exhibit autonomous pacemaking based on L-type voltage-dependent Ca²⁺ channels and show autoreceptor-dependent regulation of dopamine release. When transplanted in the striatum of 6-OHDA-lesioned athymic rats, the human A9 DA neurons manifest robust survival and axon outgrowth, and ameliorate motor deficits in the rat PD model. The ability to generate patient-specific A9 DA autonomous pacemakers will significantly improve PD research and facilitate the development of disease-modifying therapies.2022-01-01T00:00:00Z2022 Nov2025-04-05T11:28:00.557Z2025-04-05T11:28:00.557ZS-EPMC96843583561035110.1038/s41380-022-01628-1