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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (ATAC-Seq)

ABSTRACT: Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (ATAC-Seq)

PROVIDER: PRJNA506259 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8217140_1.fastq.gz	Fastqsanger.gz
	SRR8217140_2.fastq.gz	Fastqsanger.gz
	SRR8217131_1.fastq.gz	Fastqsanger.gz
	SRR8217131_2.fastq.gz	Fastqsanger.gz
	SRR8217141_1.fastq.gz	Fastqsanger.gz

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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (RNA-Seq)

Project description:Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial cells by constantly probing their surroundings with dynamic extensions. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.

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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (ATAC-Seq)

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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge

Project description:Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge

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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (RNA-Seq)

Project description:Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge (RNA-Seq)

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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge.

Project description:Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.

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Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge

Project description:This SuperSeries is composed of the SubSeries listed below.

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Brain-Engrafted Monocyte-derived Macrophages from Blood and Skull-Bone Marrow Exhibit Distinct Properties [scRNA_DR3X]

Project description:Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDM) exist at homeostasis and during turnover, and how they function relative to yolk sac-derived microglia (YSM) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDM display transcriptional and epigenetic landscapes distinct from YSM. Fate-mapping reveals that brain-engrafted MDM transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by IL-34 and CCR2. Furthermore, parabiosis and skull‑flap transplantation reveal that both blood and skull marrow supply the niche, yielding origin‑biased MDM states. Functionally, MDM engraftment enhanced cuprizone-mediated demyelination. Together, our study defines the origins, molecular features, and context-dependent roles of brain parenchymal macrophages across homeostasis, turnover, and CNS pathology.

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