Microglia heterogeneity, modeling and cell-state annotation in development and neurodegeneration
Abstract
Within the CNS, microglia execute various functions associated with brain development, maintenance of homeostasis and elimination of pathogens and protein aggregates. This wide range of activities is closely associated with a plethora of cellular states, which may reciprocally influence or be influenced by their functional dynamics. Advancements in single-cell RNA sequencing have enabled a nuanced exploration of the intricate diversity of microglia, both in health and disease. Here, we review our current understanding of microglial transcriptional heterogeneity. We provide an overview of mouse and human microglial diversity encompassing aspects of development, neurodegeneration, sex and CNS regions. We offer an insight into state-of-the-art technologies and model systems that are poised to improve our understanding of microglial cell states and functions. We also provide suggestions and a tool to annotate microglial cell states on the basis of gene expression.
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In M_2 cluster, 5XFAD;PS19 model exhibited enrichment of several marker genes associated with specific microglial states, including DAM-like, antigen presentation (HLA/MHC class II), and cytokine response microglia involved in inflammation.
“In the M_2 cluster, the 5XFAD;PS19 model also exhibited enrichment of several marker genes associated with specific microglial states, including disease‐associated microglia (DAM)‐like, antigen presentation (HLA/MHC class II), and cytokine response microglia involved in inflammation (Figure S4C–E).”
From Unique transcriptomic alterations in 5XFAD;PS19 mouse model identify glial lipid dysregulation and coordinated microglial–oligodendrocyte responses (2026) · cites this paper as [47]
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Microglial states revisited: from homeostasis to disease
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- Authors
- Fumagalli, L., Nazlie Mohebiany, A., Premereur, J., Polanco Miquel, P., Bijnens, B., Van de Walle, P., Fattorelli, N., & Mancuso, R.
- Affiliations
- University of Antwerp (BE)
- Corresponding author
- Mancuso, Renzo
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2025-04-07
- Volume
- 28
- Issue
- 7
- Pages
- 1381-1392
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W4409210053
- Cited by
- 90
- References
- 48
- Citations by year
- 2026: 67 · 2025: 23
- FWCI
- 8.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, microglial heterogeneity, brain development, neurodegeneration, single-cell RNA sequencing, transcriptional heterogeneity, sex differences, mouse model, human microglia, gene expression signatures
- MeSH terms
- Animals, Brain, Humans, Microglia, Neurodegenerative Diseases, Mice
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