Gene expression profile at single cell level of YS-derived cells and monocyte-derived cells from brain parenchyma and leptomeninges of Ms4a3-Cre: R26-TdTomato: Cx3cr1-gfp mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE282946 | GEO | 2024/12/02
REPOSITORIES: GEO
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Project description:After irradiation and bone-marrow transplantation, most of microglia and boarder-associated macrophages in the central nervous system is replaced by engranft cells. Taking advantages of Ms4a3-Cre: R26-TdTomato: Cx3cr1-gfp mice, we discriminated cells from monocyte precursors and hematopoietic stem cells with colors at 32 weeks following irradiation and bone-marrow transplantation. We sorted HSC-derived, monocyte-derived, and endogenouse microglia and leptomeningeal macrophages, and analyzed gene expression level between different cell populations using a bulk RNAseq method.
2024-12-02 | GSE282221 | GEO
Project description:Gene expression profile at single cell level of YS-derived cells and monocyte-derived cells from brain parenchyma and leptomeninges of Ms4a3-Cre: R26-TdTomato: Cx3cr1-gfp mice
| PRJNA1191140 | ENA
Project description:Perivascular and leptomeningeal macrophages are non-parenchymal macrophages summarized as central nervous system (CNS)-associated macrophages (CAMs) that mediate immune responses at brain boundaries. Both, CAMs and juxtaneuronal microglia are derived from prenatal yolk sac (YS) precursors, long-living and maintain their populations by homeostatic self-renewal without input from the periphery. Whereas microglia have been shown to be repopulated by CNS endogenous remnants of the same lineage following depletion, the renewal biology of CAMs is still poorly understood. Here, by combining multilineage myeloid fate mapping, bulk and single-cell profiling and high resolution confocal imaging, we show that the repopulation is strikingly different between CAMs and microglia. In contrast to microglia, CAMs do not renew exclusively cell-autonomously, but transiently utilize CCR2+Ly-6C+ monocytes after niche induction in an integrin-dependent manner. Remarkably and unlike repopulated microglia, replenished monocyte-derived CAMs remain transcriptionally and functionally distinct from their YS-derived counterparts. Finally, we established a protocol that allows to selectively exchange CAMs modulating disease response without functionally affecting parenchymal microglia. These new insights into the biology of the CNS immune system offer completely new therapeutic avenues for diverse neuroinflammatory and neurodegenerative diseases.
2026-03-01 | GSE318650 | GEO
Project description:Fate mapping via Ms4a3 expression history traces monocyte-derived cells
| PRJNA555482 | ENA
Project description:Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and persist throughout life without contributions from definitive hematopoiesis. Here, using Ms4a3-Cre lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and unique features of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation. Using parabiosis and skull transplantation, we show that MDMs derived from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains, and they display distinct transcriptional profiles compared to YS-derived microglia. Blood-derived macrophages possess a disease-associated microglia (DAM)-like phenotype, while skull-derived macrophages mirror injury-responsive microglia (IRM) and exhibit significant interactions with T cells. Repetitive microglia depletion and subsequent MDM engraftment in 5xFAD mice led to increased amyloid burden, suggesting differential responses of resident microglia and MDMs towards amyloid pathology. Our results reveal the heterogeneous origins and functions of microglia during cell turnover and neurodegeneration, offering insights that may guide microglia-targeted immunomodulatory strategies for neurological disorders.
2025-03-21 | GSE285072 | GEO
Project description:Background: The transcription factor EVI1 regulates cellular proliferation, differentiation, and apoptosis, and contributes to an aggressive course of disease in myeloid leukemias and other malignancies. Notwithstanding, knowledge about the target genes mediating its biological and pathological functions remains limited. We therefore aimed to identify and characterize novel EVI1 target genes in human myeloid cells. Methods: U937T_EVI1, a previously established human myeloid cell line expressing EVI1 in a tetracycline regulable manner, was subjected to genome wide gene expression microarray analysis. qRT-PCR was used to confirm the regulation of MS4A3 by EVI1. Reporter constructs containing various parts of the MS4A3 upstream region were employed in luciferase assays, and direct binding of EVI1 to the MS4A3 promoter was investigated by chromatin immunoprecipitation. U937 derivative cell lines experimentally expressing EVI1 and/or MS4A3 were generated by retroviral transduction, and tested for their tumorigenicity by subcutaneous injection into severe combined immunodeficient mice. Experimental results were tested for statistical significance using ANOVA and Student's t-test (two-tailed). Results: Gene expression microarray analysis identified 27 unique genes that were up-regulated and 29 that were down-regulated in response to EVI1 induction in the human myeloid cell line, U937. The most strongly repressed gene was membrane-spanning-4-domains subfamily-A member-3 (MS4A3), and its down-regulation by EVI1 was confirmed by qRT-PCR in additional, independent experimental model systems. Reporter gene assays and chromatin immunoprecipitation showed that EVI1 regulated MS4A3 via direct binding to a promoter proximal region. Experimental re-expression of MS4A3 in an EVI1 overexpressing cell line counteracted the tumor promoting effect of EVI1 in a murine xenograft model. Conclusions: Our data reveal MS4A3 as a novel direct target of EVI1 in human myeloid cells, and show that its repression plays a role in EVI1 mediated tumor aggressiveness. Time course of 2 biological replicates, plus 2 control samples; 20 arrays in total
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Project description:Meningeal immune cells monitor the central nervous system (CNS) and influence neuroinflammation in mice, but the human leptomeningeal immune landscape and the changes that occur in this immunological niche in neurodegeneration remain underexplored. We performed single-cell RNA and T cell receptor (TCR) sequencing of 99,625 high-quality immune cells from 57 leptomeninges and brain samples from donors with Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and Parkinson’s disease and found that while the leptomeninges are home to highly clonally expanded CD8 tissue-resident memory (TRM) T cells, the maximal level of clonal expansion was decreased in AD in comparison to non-neurodegenerative controls. Intra-patient paired tissue analysis further revealed that brain and leptomeningeal TCR repertoires share significant similarities, but tissue-specific clones emerge in AD. Finally in AD, the degree of CD8 TRM clonal expansion was positively correlated with microglial TGFB2, suggesting that brain and leptomeningeal immune cells coordinate their activities in AD. In addition to identifying key inflammatory dynamics in the human degenerating CNS, this study establishes a foundational resource for future studies that could inform treatment for AD and other neuroinflammatory diseases.
2025-11-24 | GSE288856 | GEO
Project description:Perivascular and leptomeningeal macrophages are non-parenchymal macrophages summarized as central nervous system (CNS)-associated macrophages (CAMs) that mediate immune responses at brain boundaries. Both, CAMs and juxtaneuronal microglia are derived from prenatal yolk sac (YS) precursors, long-living and maintain their populations by homeostatic self-renewal without input from the periphery. Whereas microglia have been shown to be repopulated by CNS endogenous remnants of the same lineage following depletion, the renewal biology of CAMs is still poorly understood. Here, by combining multilineage myeloid fate mapping, bulk and single-cell profiling and high resolution confocal imaging, we show that the repopulation is strikingly different between CAMs and microglia. In contrast to microglia, CAMs do not renew exclusively cell-autonomously, but transiently utilize CCR2+Ly-6C+ monocytes after niche induction in an integrin-dependent manner. Remarkably and unlike repopulated microglia, replenished monocyte-derived CAMs remain transcriptionally and functionally distinct from their YS-derived counterparts. Finally, we established a protocol that allows to selectively exchange CAMs modulating disease response without functionally affecting parenchymal microglia. These new insights into the biology of the CNS immune system offer completely new therapeutic avenues for diverse neuroinflammatory and neurodegenerative diseases.
2026-03-01 | GSE295335 | GEO
Project description:Perivascular and leptomeningeal macrophages are non-parenchymal macrophages summarized as central nervous system (CNS)-associated macrophages (CAMs) that mediate immune responses at brain boundaries. Both, CAMs and juxtaneuronal microglia are derived from prenatal yolk sac (YS) precursors, long-living and maintain their populations by homeostatic self-renewal without input from the periphery. Whereas microglia have been shown to be repopulated by CNS endogenous remnants of the same lineage following depletion, the renewal biology of CAMs is still poorly understood. Here, by combining multilineage myeloid fate mapping, bulk and single-cell profiling and high resolution confocal imaging, we show that the repopulation is strikingly different between CAMs and microglia. In contrast to microglia, CAMs do not renew exclusively cell-autonomously, but transiently utilize CCR2+Ly-6C+ monocytes after niche induction in an integrin-dependent manner. Remarkably and unlike repopulated microglia, replenished monocyte-derived CAMs remain transcriptionally and functionally distinct from their YS-derived counterparts. Finally, we established a protocol that allows to selectively exchange CAMs modulating disease response without functionally affecting parenchymal microglia. These new insights into the biology of the CNS immune system offer completely new therapeutic avenues for diverse neuroinflammatory and neurodegenerative diseases.
2026-03-01 | GSE318071 | GEO
Project description:Perivascular and leptomeningeal macrophages are non-parenchymal macrophages summarized as central nervous system (CNS)-associated macrophages (CAMs) that mediate immune responses at brain boundaries. Both, CAMs and juxtaneuronal microglia are derived from prenatal yolk sac (YS) precursors, long-living and maintain their populations by homeostatic self-renewal without input from the periphery. Whereas microglia have been shown to be repopulated by CNS endogenous remnants of the same lineage following depletion, the renewal biology of CAMs is still poorly understood. Here, by combining multilineage myeloid fate mapping, bulk and single-cell profiling and high resolution confocal imaging, we show that the repopulation is strikingly different between CAMs and microglia. In contrast to microglia, CAMs do not renew exclusively cell-autonomously, but transiently utilize CCR2+Ly-6C+ monocytes after niche induction in an integrin-dependent manner. Remarkably and unlike repopulated microglia, replenished monocyte-derived CAMs remain transcriptionally and functionally distinct from their YS-derived counterparts. Finally, we established a protocol that allows to selectively exchange CAMs modulating disease response without functionally affecting parenchymal microglia. These new insights into the biology of the CNS immune system offer completely new therapeutic avenues for diverse neuroinflammatory and neurodegenerative diseases.
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