Lipopolysaccharide distinctively alters human microglia transcriptomes to resemble microglia from Alzheimer's disease mouse models.
ATPγS
Alzheimer's disease
IFN-γ
LPS
PGE2
iPSC-microglia
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
received:
19
10
2021
accepted:
30
08
2022
entrez:
18
10
2022
pubmed:
19
10
2022
medline:
20
10
2022
Statut:
ppublish
Résumé
Alzheimer's disease (AD) is the most common form of dementia, and risk-influencing genetics implicates microglia and neuroimmunity in the pathogenesis of AD. Induced pluripotent stem cell (iPSC)-derived microglia (iPSC-microglia) are increasingly used as a model of AD, but the relevance of historical immune stimuli to model AD is unclear. We performed a detailed cross-comparison over time on the effects of combinatory stimulation of iPSC-microglia, and in particular their relevance to AD. We used single-cell RNA sequencing to measure the transcriptional response of iPSC-microglia after 24 h and 48 h of stimulation with prostaglandin E2 (PGE2) or lipopolysaccharide (LPS)+interferon gamma (IFN-γ), either alone or in combination with ATPγS. We observed a shared core transcriptional response of iPSC-microglia to ATPγS and to LPS+IFN-γ, suggestive of a convergent mechanism of action. Across all conditions, we observed a significant overlap, although directional inconsistency to genes that change their expression levels in human microglia from AD patients. Using a data-led approach, we identify a common axis of transcriptomic change across AD genetic mouse models of microglia and show that only LPS provokes a transcriptional response along this axis in mouse microglia and LPS+IFN-γ in human iPSC-microglia. This article has an associated First Person interview with the first author of the paper.
Identifiants
pubmed: 36254682
pii: 277958
doi: 10.1242/dmm.049349
pmc: PMC9612871
pii:
doi:
Substances chimiques
Lipopolysaccharides
0
Interferon-gamma
82115-62-6
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MC_EX_MR/N50192X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0902227
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K013041/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300429
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L501517/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 100643/Z/12/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17112
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_16034
Pays : United Kingdom
Informations de copyright
© 2022. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests M.Z.C. is co-founder and director of Oxford StemTech Ltd. and HumanCentric DD Ltd. C.W. is co-founder and director of HumanCentric DD Ltd.
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