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Direct Conversion of Human Umbilical Cord Mesenchymal Stem Cells into Dopaminergic Neurons for Parkinson's Disease Treatment

ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits resulting from the depletion of nigrostriatal dopamine. Stem cell differentiation therapy is a promising treatment option for achieving sustained relief from symptoms. In this study, we successfully established a one-step differentiation system using the YFBP cocktail (Y27632, Forskolin, SB431542, and SP600125) to efficiently convert human umbilical cord mesenchymal stem cells (hUCMSCs) into dopaminergic neurons, avoiding the need for genetic modification. This approach addresses the challenge of generating functional neurons rapidly and safely on a large scale. Following a 7-day induction period, the proportion of TUBB3 and NEUN double-positive cells exceeded 80%. Transcriptome analysis revealed the dual roles of the cocktail in inducing fate erasure in MSCs and activating the neuronal program. Notably, the differentiated derivatives did not express HLA class II genes, preserving their immune-privileged status. Additionally, YFBP significantly downregulated p53 signaling, accelerating the differentiation process upon signaling inhibition with pifithrin-α. Wnt/β-catenin signaling was transiently activated within 1 day, with prolonged activation hindering the cascade. After being transplanted into the striatum of mice, YFBP-induced dopaminergic neurons survived well and exhibited neuronal electrophysiological activity, effectively reversing movement disorders in PD animals. In conclusion, our research offers a secure and reliable framework for cell replacement therapy and regenerative medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268939 | GEO | 2025/12/19

REPOSITORIES: GEO

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