Authors
Chaplot, K., Zhang, L., Wessman, J., Rivera, M., Wang, Z., Wang, F., Duan, X., England, P. M., Clark, I. C., Ullian, E. M.
Abstract
In vitro modelling of highly vulnerable nigral dopaminergic (DA) neuronal subtypes in Parkinson's disease (PD), is necessary for studying disease mechanisms. Here, we optimized a new approach by expressing the pioneer neurogenic transcription factor, Achaete-scute-like 1 (Ascl1), implicated in determining dopaminergic fate. Sequential small-molecule patterning of iPSCs into early floor plate mesencephalic progenitors, followed by inducible Ascl1 expression, rapidly differentiates midbrain DA neurons. Immunocytochemistry and transcriptomic analysis of these patterned Ascl1-driven DA neurons (PA-DANs) confirmed midbrain-lineage specificity. Importantly, we found an enrichment of DA subpopulations that corresponded to the adult human ventral SOX6-positive A9 DA subtypes vulnerable in PD. Furthermore, we combined these ventral A9-like PA-DANs with human iPSC-derived midbrain astrocytes and microglia in defined ratios to generate mature 3D A9-like assembled organoids that display characteristic spontaneous neuronal activity and electrical propagation along the axon. Our method efficiently generates a mature and functional A9-like DA neuronal platform to study PD.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Nov 2025.
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