ArticleTissue engineering and regenerative medicine2026
Potentiated Maturation of hPSC-Derived Dopaminergic Neurons via Convergent Genetic and Small Molecule Modulation.
Article in Tissue engineering and regenerative medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundVentral midbrain dopaminergic (vmDA) neurons derived from human pluripotent stem cells provide a powerful platform for modeling Parkinson's disease (PD) and developing therapeutic strategies. Although robust protocols exist for generating vmDA progenitors, maturation into functionally competent neurons typically requires prolonged culture periods and occurs with substantial heterogeneity in maturity, representing major bottlenecks.
methodsBuilding on established protocols for vmDA progenitor differentiation, we introduce a sequential strategy that specifically targets the subsequent phases of neuronal conversion and postmitotic maturation. Transient overexpression of the proneural transcription factor achaete-scute family bHLH transcription factor 1 (ASCL1) was applied to human embryonic stem cell-derived vmDA progenitors to induce neuronal commitment, followed by accelerated postmitotic maturation using the small-molecule cocktail GENtoniK. This approach was evaluated in CRISPR/Cas9-engineered human induced pluripotent stem cell (hiPSC) lines lacking either PINK1 or PRKN and their isogenic control hiPSCs.
resultsTransient ASCL1 overexpression promoted rapid cell cycle exit and neuronal conversion of vmDA progenitors while preserving ventral midbrain identity and dopaminergic fate. Subsequent GENtoniK treatment enhanced postmitotic dopaminergic maturation and increased neurite complexity, synaptic organization, and dopaminergic neurotransmission without altering lineage specification. Consequently, within two weeks, our protocol yielded high-purity vmDA neurons with enhanced functional maturation from vmDA progenitors. Importantly, PINK1- and PRKN-deficient neurons generated from CRISPR/Cas9-engineered hiPSC lines using this strategy recapitulated key PD-associated mitochondrial phenotypes, including impaired mitophagy, mitochondrial dysfunction, and elevated oxidative stress.
conclusionTaken together, these findings address the central limitations of current dopaminergic differentiation paradigms by enabling the rapid and uniform acquisition of advanced functional maturity, thereby providing a robust platform for disease modeling and translational research in PD.
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