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Cited by 380Neuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanismsPluripotent Stem Cells Research

Development of a Chimeric Model to Study and Manipulate Human Microglia In Vivo

Open access
Hasselmann, Jonathan, Coburn, Morgan A., England, Whitney, Figueroa Velez, Dario X., Kiani Shabestari, Sepideh, Tu, Christina H., McQuade, Amanda, Kolahdouzan, Mahshad +13 more·2019·Neuron
DOI 10.1016/j.neuron.2019.07.002PMC PMC7138101
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Abstract

iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Aβ-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Aβ-responsive genes. We therefore have demonstrated that this chimeric model provides a powerful new system to examine the in vivo function of patient-derived and genetically modified microglia.

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  • A previously published dataset shows that ACSL1 is highly upregulated by the innate immune trigger lipopolysaccharides in an independent human iMG chimaeric mouse model.

    “A previously published dataset shows that ACSL1 is highly upregulated by the innate immune trigger lipopolysaccharides (LPS) in an independent human iMG chimaeric mouse model22”

    From APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia (2024) · cites this paper as [22]

    The Results section, “xMGs respond robustly to a systemic inflammatory challenge” (page not available), reports a dataset comparing human microglia from saline- and LPS-treated chimeric mice and identifies 607 upregulated genes. Our copy does not identify ACSL1 among them or establish that it was highly upregulated; searches for ACSL1 and its full gene name found no supporting passage. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The chimeric transplantation approach has been validated in prior work.

    “For further details and validation of this chimeric approach please see Hasselmann et al. 14”

    From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [14]

  • MITRG and hCSF1 mice enable equivalent engraftment and survival of human iPSC-derived microglia, as the presence of the humanized CSF1 allele is necessary whereas inclusion of the CSF2 and TPO alleles are dispensable.

    “We recently confirmed that MITRG and hCSF1 mice enable equivalent engraftment and survival of human iPSC‐derived microglia as the presence of the humanized CSF1 allele is necessary whereas inclusion of the CSF2 and TPO alleles are dispensable. 14”

    From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [14]

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Research works printed but not linked: 38

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Authors
Hasselmann, J., Coburn, M. A., England, W., Figueroa Velez, D. X., Kiani Shabestari, S., Tu, C. H., McQuade, A., Kolahdouzan, M., Echeverria, K., Claes, C., Nakayama, T., Azevedo, R., Coufal, N. G., Han, C. Z., Cummings, B. J., Davtyan, H., Glass, C. K., Healy, L. M., Gandhi, S. P., Spitale, R. C., & Blurton-Jones, M.
Affiliations
  • University of California, Irvine (US)
  • Montreal Neurological Institute and Hospital (CA)
  • University of California San Diego (US)
Corresponding author
Blurton-Jones, Mathew
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2019-09
Volume
103
Issue
6
Pages
1016-1033.e10
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2019.07.002
PMC
PMC7138101
OpenAlex
W2964755252
Cited by
380
References
66
Citations by year
2026: 46 · 2025: 59 · 2024: 66 · 2023: 41 · 2022: 55 · 2021: 48 · 2020: 57 · 2019: 7
FWCI
18.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (R01 DA048813)
  • Innovative Medicines Initiative (WO/2018/160496, 115582)
  • National Institute on Aging (NS082174, F31EY028046, AG00096)
  • California Institute for Regenerative Medicine (RT3-07893, UCI MIND/WAM 01-2018)
  • Cancer Research Institute
  • National Institute of Neurological Disorders and Stroke (K08NS109200)
  • Foundation for the National Institutes of Health (F31EY028046, AG00096, NS082174, 1S10OD021718-01, 1S10RR025496-01, 1S10OD010794-01, T32GM008620, EY029596-02, P30CA-062203)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
human microglia, iPSC-derived microglia, chimeric mouse model, microglial differentiation, amyloid plaques, microglial transcriptome, neuroinflammation, CNS macrophages
MeSH terms
Alzheimer Disease, Animals, Brain, Cell Differentiation, Disease Models, Animal, Humans, Mice, Transgenic, Thrombopoietin, Gene Expression, Macrophage Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, Amyloid beta-Peptides, Microglia, Transplantation Chimera, Hematopoietic Stem Cell Transplantation, Mice, Induced Pluripotent Stem Cells, Plaque, Amyloid

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