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Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

ABSTRACT: Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

PROVIDER: PRJNA842352 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19396181_1.fastq.gz	Fastqsanger.gz
	SRR19396181_2.fastq.gz	Fastqsanger.gz
	SRR19396182_1.fastq.gz	Fastqsanger.gz
	SRR19396182_2.fastq.gz	Fastqsanger.gz
	SRR19396183_1.fastq.gz	Fastqsanger.gz

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Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

Project description:Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

| PRJNA842351 | ENA

Human midbrain dopaminergic neuronal differentiation markers predict cell therapy outcome in a Parkinson's disease model

Project description:Human pluripotent stem cell (hPSC)-based replacement therapy holds great promise in treating Parkinson’s disease (PD). However, the heterogeneity of hPSC-derived donor cells and the low yield of midbrain dopaminergic (mDA) neurons after transplantation hinder its broad clinical application. Here, we depicted the single-cell molecular landscape during mDA neuron differentiation. We found that this process recapitulated the development of multiple but adjacent fetal brain regions including ventral midbrain, isthmus, and ventral hindbrain, resulting in heterogenous donor cell population. We reconstructed the differentiation trajectory of mDA lineage and identified CLSTN2 and PTPRO as specific surface markers of mDA progenitors, which were predictive of mDA neuron differentiation and could facilitate highly enriched mDA neurons (up to 80%) following progenitor sorting and transplantation. Marker sorted progenitors exhibited higher therapeutic potency in correcting motor deficits of PD mice. Different marker sorted grafts had a strikingly consistent cellular composition, in which mDA neurons were enriched, while off-target neuron types were mostly depleted, suggesting stable graft outcomes. Our study provides a better understanding of cellular heterogeneity during mDA neuron differentiation, and establishes a strategy to generate highly purified donor cells to achieve stable and predictable therapeutic outcomes, raising the prospect of hPSC-based PD cell replacement therapies.

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