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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE122766 | GEO | 2018/11/21

REPOSITORIES: GEO

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

2018-11-21 | GSE122768 | GEO

Early fate defines microglia and non-parenchymal brain macrophage development

Project description:Central nervous system (CNS) macrophages comprise parenchymal microglia and border-associated macrophages (BAMs) residing in the meninges, the choroid plexus and the perivascular spaces. With the exception of choroid plexus macrophages, most CNS macrophages emerge during primitive hematopoiesis in the extra-embryonic yolk sac. What remains unknown however, is whether microglia and BAMs share a developmental program or arise from separate predefined lineages. Here, we identified two phenotypically, transcriptionally and locally distinct brain macrophage populations throughout development, giving rise to microglia and BAMs. Two independent macrophage populations were already present in the yolk sac prior to their seeding of the brain. Using fate-mapping system, we demonstrate that in contrast to microglia, the pool of embryonic BAMs in the choroid plexus and the meninges was gradually replaced by precursors emerging later in embryogenesis. The development of microglia was dependent on TGF-β whereas the genesis and maturation of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages are separate entities in terms of ontogeny, gene expression signatures and requirement for TGF-β.

2020-04-15 | GSE146926 | GEO

Early fate defines microglia and non-parenchymal brain macrophage development

2020-04-16 | GSE146928 | GEO

Comparative genomic analysis of basal and LPS-induced expression patterns of bone marrow derived macrophages and bone marrow resident macrophages

Project description:Comparative genomic analysis of basal and LPS-induced expression patterns of bone marrow derived macrophages and bone marrow resident macrophages demonstrates completely divergent transcriptome profile and indicates/confirms the existance of two distinct monocyte/macrophage populations in murine bone marrow. Most resident tissue macrophages descent from embryonic precursors of the yolk sac but inflammatory and bone marrow (BM) macrophages are considered to develop from hematopoietic stem cells (HSCs) in the BM. We now identified a novel subpopulation of resident CD163+ macrophages in the BM which were phenotypically and functionally distinct from classical BM-derived macrophages. Bioinformatics analysis of transcriptoms indicated a unique immune-modulatory phenotype of CD163+ macrophages. Cell fate studies in Csf1rMer-iCre-Mer;RosaLSL-GFP mice demonstrated that resident CD163+ macrophages of the BM do not develop from HSCs but descent from embryonic progenitors in the yolk sac strictly dependent on transcription factor IRF8. In contrast to other yolk sac derived tissue macrophages CD163+ cells seem to play a relevant role in infections and sterile inflammation. IRF8-/- mice lacking this population are highly sensible to S. aureus infections. Thus, CD163 defines a macrophage population resident in the bone marrow but originating from yolk sac progenitors which exhibits immune-modulatory properties under different inflammatory conditions. We used quantitative RNA-seq to perform whole transcriptome analysis and compare the transcriptomes of resident CD163+ BM macrophages and classical CD163- BMDM in steady state and after LPS stimulation.

2017-01-31 | GSE92618 | GEO

Induced pluripotent stem cell-derived primitive macrophages as a cellular platform to model tissue-resident macrophage differentiation and function

Project description:Specialized tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that migrate into developing tissues and terminally differentiate in situ. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process reminiscent of YS-hematopoiesis in vitro. We asked whether iPSC-derived primitive macrophages (iMac) can terminally differentiate into specialized macrophages using growth factors and organ-specific cues. Co-culturing murine iMac with iPSC-derived neurons promoted differentiation into microglia-like cells in vitro. Furthermore, murine iMac differentiated in vivo into microglia following injection into the brain, and functional alveolar macrophages after engraftment in the lung.

2017-07-20 | GSE99078 | GEO

C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages

Project description:Although classified as hematopoietic cells, tissue-resident macrophages are selfrenewing and maintained independently of adult hematopoiesis. While most macrophages originate from embryonic precursors that seed tissues prior to birth, their exact origin is unknown. Using an in utero macrophage depletion strategy and fatemapping of yolk sac (YS) and fetal liver (FL) hematopoiesis, we found that YS macrophages are the main precursors of microglia, while most other macrophages derive from fetal monocytes. Both YS macrophages and fetal monocytes arise from erythro-myeloid progenitors (EMP) generated in the YS. In the YS, EMP gave rise to macrophages without monocytic intermediates, while EMP seeding the FL upon the establishment of blood circulation acquired c-Myb expression and gave rise to fetal monocytes that then seed embryonic tissues to differentiate into macrophages. Thus, adult tissue-resident macrophages established from HSC-independent embryonic precursors arise from two different developmental programs. 12 samples of progenitors, monocytes or macrophages are analyzed from 2 to 4 replicate. Each replicate derived from at least 5 embryos or adult mice

2015-04-23 | E-GEOD-66970 | biostudies-arrayexpress

Brain microglia are maintained and regenerated from a specialized cellular subset

Project description:Microglia, macrophages of the brain parenchyma, are essential for normal brain development and function as well as local immune responses. However, they can also induce and perpetuate severe brain pathology in certain conditions. Microglia are derived from early, fetal yolk sac (YS) progenitors and they are then maintained locally behind the blood brain barrier (BBB) without any external cellular input. It is thought that all microglia cells, like many other tissue-resident macrophages, have self-renewal capacity to maintain its cellularity. Here we, however, report an identification of a minor microglial stem cell-like cells (MgSCs) that are responsible of microglia expansion and maintenance during development and during steady state. MgSCs resemble somatic, unipotent stem cells: they are self-renewing and able to differentiate to the bulk of sessile microglia which , on the need , can dedifferentiate back to MgSCs. Due to their central role in microglia turnover MgSCs can become valuable, therapeutic targets in neuropathological conditions.

2018-12-01 | GSE79060 | GEO

Interleukin-1 signaling is involved in local self-renewal and maintenance of microglia

Project description:During early embryogenesis microglia arise from yolk sac progenitors populating the developing CNS, where they are maintained as tissue-resident macrophages throughout the organism’s lifespan. Here, we describe an experimental system that allows the specific conditional ablation of microglia in vivo. Strikingly, we found that the microglia compartment was reconstituted within one week following depletion. Microglia repopulation relied entirely on a CNS-resident, internal pool and was independent from bone marrow-derived precursors. Newly formed microglia were found in highly proliferative, organized micro-clusters that dissolve once steady state was achieved. Gene expression profiling revealed prominent expression of Interleukin-1 (IL-1) receptor in proliferating microglia. During the repopulation phase, IL-1 signaling was neutralized by treatment with IL-1 receptor antagonist that impaired microglia proliferation. Hence, microglia harbor a highly efficient potential to restore themselves without contribution of peripheral myeloid cells. IL-1 signaling significantly participates in this restorative proliferation process and is involved in stabilizing microglia maintenance. bone marrow macrophages, wild type microglia, and repopulating microglia

2015-07-15 | E-GEOD-68376 | biostudies-arrayexpress

GomezElisa_AgilentMouse

Project description:Macrophages and dendritic cells (DC) are key components of cellular immunity and, as per the current model, originate from hemopoietic stem cells (HSCs). However, microglia were recently shown to originate from precursors that precede the appearance of HSCs. We thus re-investigated macrophage development and their relationship to HSCs and yolk sac (YS) precursors.

2012-03-15 | E-MEXP-3510 | biostudies-arrayexpress

Maternal Diet During Early Gestation Influences Postnatal Taste Activity-Dependent Pruning By Microglia

Project description:Microglia aid in refining central gustatory circuits during normal development. This process is arrested by merely restricting their mother’s dietary sodium during a limited, early prenatal period when microglia progenitors migrate from the yolk-sac to the brain.

2023-08-14 | GSE239942 | GEO

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