Stem-cell-derived human microglia transplanted in mouse brain to study human disease
Open accessPublished version of a preprint
Abstract
Although genetics highlights the role of microglia in Alzheimer's disease, one-third of putative Alzheimer's disease risk genes lack adequate mouse orthologs. Here we successfully engraft human microglia derived from embryonic stem cells in the mouse brain. The cells recapitulate transcriptionally human primary microglia ex vivo and show expression of human-specific Alzheimer's disease risk genes. Oligomeric amyloid-β induces a divergent response in human versus mouse microglia. This model can be used to study the role of microglia in neurological diseases.
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The single-cell protocol performed dissociation at 4°C to mitigate potential activation, making it unlikely that dissociation procedures account for the differences.
“For our single-cell protocol, we performed dissociation at 4°C to mitigate potential activation (Mancuso et al., 2019), so it is unlikely the dissociation procedures account for the differences.”
From Single-Nucleus RNA-Seq Is Not Suitable for Detection of Microglial Activation Genes in Humans (2020) · cites this paper as Mancuso et al., 2019
The Methods section, “Isolation of human and mouse microglia from the mouse brain” (page unavailable), describes tissue dissociation followed by centrifugation and antibody labeling at 4°C. It does not say dissociation itself was performed at 4°C or that cold processing mitigated activation. The conclusion about the citing authors’ own differences is not attributed to Mancuso et al. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThese soluble Aβ aggregate species induce a cytokine response in Apoe-deficient microglia.
“These species induce a cytokine response (Mancuso et al, 2019) in the Apoe-deficient microglia.”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Mancuso et al, 2019
The Results section (‘Human ESC-derived and host mouse microglia display a divergent response to oligomeric Aβ’; page unavailable) reports a cytokine-response cluster enriched after oligomeric Aβ treatment. It does not establish that the responding microglia were Apoe-deficient; the host mice described there were Rag2- and Il2rγ-deficient. (LLM, conf=0.86)
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References 50 · Cited by 295
Research works printed but not linked: 14
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- Authors
- Mancuso, R., Van Den Daele, J., Fattorelli, N., Wolfs, L., Balusu, S., Burton, O., Liston, A., Sierksma, A., Fourne, Y., Poovathingal, S., Arranz-Mendiguren, A., Sala Frigerio, C., Claes, C., Serneels, L., Theys, T., Perry, V. H., Verfaillie, C., Fiers, M., & De Strooper, B.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Leuven Stem Cell Institute (BE)
- KU Leuven (BE)
- UK Dementia Research Institute (GB)
- Corresponding author
- Mancuso, Renzo
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-10-28
- Volume
- 22
- Issue
- 12
- Pages
- 2111-2116
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC7616913
- OpenAlex
- W2982115290
- Cited by
- 295
- References
- 50
- Citations by year
- 2026: 34 · 2025: 43 · 2024: 50 · 2023: 49 · 2022: 47 · 2021: 36 · 2020: 33 · 2019: 3
- FWCI
- 13.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Alzheimer's Association
- Alzheimer Society
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Onderzoeksraad, KU Leuven
- Vlaamse regering
- Fondation pour la Recherche sur Alzheimer
- Medical Research Council
- Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0428, BBS/E/B/000C0427)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Alzheimer's disease, embryonic stem cells, chimeric mouse model, amyloid-beta oligomers, microglial transcriptome, human-mouse differences, neurodegenerative disease models
- MeSH terms
- Alzheimer Disease, Animals, Cell Differentiation, Female, Humans, Male, Mice, Transgenic, Amyloid beta-Peptides, Microglia, Mice, Embryonic Stem Cells, Transcriptome
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