ArticleThe Journal of experimental medicine2023
Engineering an inhibitor-resistant human CSF1R variant for microglia replacement.
Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 91 citations in OpenAlex.
- Article
- Translational modelling of human microglia from cultures to chimeras.Experimental & molecular medicine · 2026Review
- Cell Death in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.MedComm · 2026Review
- Transplantation of human iPSC-derived microglia ameliorates neuropathology and circuit dysfunction in progranulin-deficient mice.Molecular neurodegeneration · 2026Article
- CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination.Acta neuropathologica communications · 2026Article
- Brain-engrafted monocyte-derived macrophages from blood and skull-bone marrow exhibit distinct properties.Neuron · 2026Article
- Microglia in systemic neuroimmune communication: functions beyond phagocytosis.Trends in immunology · 2026Review
- Targeting amyloid-β pathology by chimeric antigen receptor astrocyte (CAR-A) therapy.Science (New York, N.Y.) · 2026Article
- Microglia replacement by peripheral delivery of CSF1R inhibitor-resistant hematopoietic cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice.Research square · 2026Article
- Article
- Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice.bioRxiv : the preprint server for biology · 2026Article
- Basic Microglial Functions and How They Go Awry in Neurodegenerative Disease.Annual review of pathology · 2026Review
- A myeloid trisomy 21-associated gene variant is protective from Alzheimer's disease.Nature neuroscience · 2026Article
- Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma.Cell death & disease · 2025Article
- Neonatal microglia replacement in mice modulates seizure severity in adulthood.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Roles of TREM2 in Alzheimer's disease.Translational neurodegeneration · 2025Review
- Controlled Delivery of a Neurotrophic Factor in the Adult Mouse Brain Using Engineered Microglia.bioRxiv : the preprint server for biology · 2025Article
- Global human myeloid replacement with peripheral progenitors induces interferonopathy and neurodegeneration.Research square · 2025Article
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Authors and funding
22 authors at 6 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.