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Engineering an inhibitor resistant human CSF1R variant for microglia replacement

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220215 | GEO | 2022/12/21

REPOSITORIES: GEO

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Engineering an inhibitor-resistant human CSF1R variant for microglia replacement.

Project description:Hematopoietic stem cell transplantation (HSCT) can replace endogenous microglia with circulation-derived macrophages but has high mortality. To mitigate the risks of HSCT and expand the potential for microglia replacement, we engineered an inhibitor-resistant CSF1R that enables robust microglia replacement. A glycine to alanine substitution at position 795 of human CSF1R (G795A) confers resistance to multiple CSF1R inhibitors, including PLX3397 and PLX5622. Biochemical and cell-based assays show no discernable gain or loss of function. G795A- but not wildtype-CSF1R expressing macrophages efficiently engraft the brain of PLX3397-treated mice and persist after cessation of inhibitor treatment. To gauge translational potential, we CRISPR engineered human-induced pluripotent stem cell-derived microglia (iMG) to express G795A. Xenotransplantation studies demonstrate that G795A-iMG exhibit nearly identical gene expression to wildtype iMG, respond to inflammatory stimuli, and progressively expand in the presence of PLX3397, replacing endogenous microglia to fully occupy the brain. In sum, we engineered a human CSF1R variant that enables nontoxic, cell type, and tissue-specific replacement of microglia.

| S-EPMC9814156 | biostudies-literature

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 [InVivo_RNA]

Project description: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.

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Engineering an inhibitor resistant human CSF1R variant for microglia replacement

Project description:Engineering an inhibitor resistant human CSF1R variant for microglia replacement

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

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

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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

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