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Engineering an inhibitor resistant human CSF1R variant for microglia replacement [InVivo_RNA]

ABSTRACT: iPSC-derived hematopoietic progenitor cells expressing either the wildtype or G795A CSF1R variant were xenotransplanted into neonatal mice and subsequently aged for two months to compare in vivo gene expression differences between the two CSF1R genotypes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220214 | GEO | 2022/12/21

REPOSITORIES: GEO

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Engineering an inhibitor resistant human CSF1R variant for microglia replacement [InVitro_RNA]

Project description:iPSC-derived microglia expressing the wildtype, G795A, or G795C CSF1R variants were generated in vitro and treated with either DMSO or Plexxicon 5622 in order to compare the gene expression differences exising between genotypes at baseline or following CSF1R inhibtion.

2022-12-21 | GSE220213 | GEO

Engineering an inhibitor resistant human CSF1R variant for microglia replacement

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

2022-12-21 | GSE220215 | GEO

single-cell RNA-seq profile of adult microglia under acute Csf1r inhibition and early repopulation

Project description:Microglia are the resident myeloid cell in the central nervous system (CNS). Like other terminally differentiated myeloid cells, microglia rely on Csf1r signaling for survival and maintenance. Surprisingly, a small subset of microglia in the murine brain can survive without Csf1r signaling, as shown in Csf1r KO mice as well as in mice that have been treated with Csf1r inhibitor PLX5622. The nature of such Csf1r independent microglial population has not been fully characterized. Here we applied single-cell RNA-seq to examine the remaining microglia in C57/BL6J mice that were treated with PLX5622 diet (1200 mg/kg, 14 days), which results >90% microglial removal.

2019-12-01 | GSE133773 | GEO

Zebrafish control and csf1r mutant microglia transcriptomes

Project description:Zebrafish control and csf1r mutant microglia transcriptomes

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Zebrafish control and csf1r mutant microglia transcriptomes

Project description:Purpose: Identify zebrafish control and csf1r-mutant microglia transcriptomes Methods: RNA sequencing was performed on FACS-sorted control microglia (3x), csf1ra-/- microglia (3x) and csf1ra-/-;b+/- microglia (3x). 10-20 million reads per sample were obtained. Reads were mapped to zebrafish genome GRC10. Results: We identified that csf1ra-/- or csf1ra-/-;b+/- microglia transcriptomes retain most of the microglia gene expression signature but mostly show changes in chemoklines expression.

2018-07-20 | GSE116215 | GEO

single-cell RNA-seq profile of microglia under acute Csf1r inhibition and early repopulation in adult brain

2020-05-09 | GSE150169 | GEO

Differential CSF1R signaling enables widespread integration of genetically unmodified human microglia into the mouse brain

Project description:Microglia are long-lived myeloid cells in the central nervous system that are implicated in many neurological diseases. The differentiation of pluripotent stem cells provides an opportunity to develop in vitro human cellular models carrying disease gene mutations complementing existing animal models of disease. Microglia are particularly sensitive to their cellular environment and can adopt a variety of reactive states depending on different pathological conditions which may be difficult to mimic in vitro. Therefore, to best investigate human microglia in vivo, it would be helpful to generate mice whose endogenous microglia are exchanged with human cells without the need of genetic manipulation of donor cells which could alter microglia function. Colony stimulating factor 1 receptor (CSF1R) signaling is critical for microglial survival in mice, and humans with CSF1R mutations are born with fewer microglia. We made the surprising discovery that transplanted human pluripotent stem cell-derived microglia (hMG) survive pharmacological CSF1R inhibition unlike endogenous mouse microglia. Cellular assays confirmed that CSF1R signaling is necessary for human microglia survival and revealed differential CSF1R signaling with species-specific ligands. Moreover, receptor ligands and small molecule inhibitors acted in a competitive fashion. Based on these insights, we found that transient CSF1R inhibition after cell transplantation led to near-complete and wide-spread repopulation of hMGs into the mouse brain of immunodeficient mice with humanized CSF1 ligand. This approach allows the facile generation of mice whose brain microglia are replaced with genetically unmodified human cells.

2024-04-11 | GSE263618 | GEO

Zebrafish control and csf1r mutant microglia and brain transcriptomes

Project description:Zebrafish control and csf1r mutant microglia and brain transcriptomes

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Gene expression data of CSF1R antibody-treated myeloma-associated macrophages

Project description:Colony-stimulating factor 1 receptor (CSF1R) signaling controls MФ differentiation and function, and blocking CSF1R exerts antitumor effects in solid tumors. We examined the effects of CSF1R blockade on multiple therapy. Our results showed that CSF1R blockade inhibited the differentiation, proliferation and survival of M2 and myeloma-associated MФs (MAMs). Microarray was used for determining CS7 effect on polarization of MAMs. We used microarrays to detail the global programme of gene expression underlying polarizaiton of myeloma-associated macrophages by CSF1R antibody treatment and identified distinct classes of polarization-related genes during this process.

2017-06-30 | GSE99393 | GEO

Systematic comparison of culture media uncovers phenotypic shift of primary human microglia defined by reduced reliance to CSF1R signaling

Project description:Efforts to understand microglia function in health and diseases have been hindered by the lack of culture models that recapitulate in situ cellular properties. In recent years, the use of serum-free media with brain-derived growth factors (CSF1R ligands and TGF-b1/2) have been favored for the maintenance of rodent microglia as they promote morphological features observed in situ. Here we study the functional and transcriptomic impacts of such media on human microglia. Media formulation had little impact on microglia transcriptome assessed by RNA sequencing which was sufficient to significantly alter microglia capacity to phagocytose myelin debris and to elicit an inflammatory response to lipopolysaccharide. When compared to immediately ex vivo microglia from the same donors, the addition of fetal bovine serum to culture media, but not growth factors, was found to aid in the maintenance of key signature genes including those involved in phagocytic processes. A phenotypic shift characterized by CSF1R downregulation in culture correlated with a lack of reliance on CSF1R signaling for survival. Consequently, no improvement in cell survival was observed following culture supplementation with CSF1R ligands. Our study provides better understanding of human microglia in culture, with observations that diverge from those previously made in rodent microglia.

2023-04-05 | GSE228755 | GEO

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