Generation of human A9 dopaminergic pacemakers from induced pluripotent stem cells
Molecular psychiatry(2022)
Abstract
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 Ca 2+ 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.
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Key words
Neuroscience,Stem cells,Medicine/Public Health,general,Psychiatry,Neurosciences,Behavioral Sciences,Pharmacotherapy,Biological Psychology
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