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High-throughput characterization of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing

ABSTRACT: High-throughput characterization of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing

PROVIDER: PRJNA832946 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18961214.fastq.gz	Fastqsanger.gz
	SRR18961215.fastq.gz	Fastqsanger.gz
	SRR18961216.fastq.gz	Fastqsanger.gz
	SRR18961217.fastq.gz	Fastqsanger.gz
	SRR18961218.fastq.gz	Fastqsanger.gz

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High-throughput characterization of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing

Project description:Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases have remained largely unexplored. Here, we firstly comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC-derivatives in mice. We then generated a high-resolution single cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature which is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson’s disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.

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High-throughput analysis of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing.

Project description:Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases, have remained largely unexplored. Here, we comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC derivatives in mice. We generated a high-resolution single-cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature that is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson's disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of transgenic protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.

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