Developmentally Guided Differentiation of Ventral Midbrain Dopaminergic Cells Validated in Proteopathy-Based Parkinson's Disease Models.

ABSTRACT: Parkinson's disease (PD) involves progressive degeneration of nigrostriatal ventral midbrain dopaminergic (vmDA) neurons and Lewy body proteopathy, necessitating scalable, lineage-faithful 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-positive vmDA progenitors through temporally optimized SHH, WNT/β-catenin, and FGF8 signaling. The resulting progenitors mature into vmDA neurons exhibiting stimulus-dependent dopamine release and maturation-associated pacemaking activity. Progenitors can be cryopreserved at a defined stage while retaining viability and neurogenic capacity. Functional va

SUBMITTER: Moon H 

PROVIDER: S-EPMC13624424 | biostudies-literature | 2026 Sep

REPOSITORIES: biostudies-literature