PreprintCited by 2,225Neuroinflammation and Neurodegeneration MechanismsSingle-cell and spatial transcriptomicsMultiple Sclerosis Research Studies

The DOI matches its Crossref record, with a small difference in title or year; 84 of the 84 references it cites were found in a registry or an index; none of the 32 sources its claims cite is checked for support yet.

Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain

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Hammond, Timothy R., Dufort, Connor, Dissing-Olesen, Lasse, Giera, Stefanie, Young, Adam, Wysoker, Alec, Walker, Alec J., Segel, Michael, Nemesh, James, Saunders, Arpiar, Macosko, Evan, Franklin, Robin J. M., Piao, Xianhua, McCarroll, Steve, Stevens, Beth·2018·Immunity

DOI 10.1101/406140PMC PMC6655561

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Abstract

Microglia, the resident immune cells of the brain, rapidly change states in response to their environment, but we lack molecular and functional signatures of different microglial populations. In this study, we analyzed the RNA expression patterns of more than 76,000 individual microglia during development, old age and after brain injury. Analysis uncovered at least nine transcriptionally distinct microglial states, which expressed unique sets of genes and were localized in the brain using specific markers. The greatest microglial heterogeneity was found at young ages; however, several states - including chemokine-enriched inflammatory microglia - persisted throughout the lifespan or increased in the aged brain. Multiple reactive microglial subtypes were also found following demyelinating injury in mice, at least one of which was also found in human MS lesions. These unique microglia signatures can be used to better understand microglia function and to identify and manipulate specific subpopulations in health and disease.

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Written from the paper’s full text.

TL;DR

Single-cell RNA sequencing of 76,149 mouse microglia across development, aging, and demyelinating injury identifies at least nine transcriptionally distinct microglial states, with the greatest diversity early in development and state shifts in aging and injury. The study defines state-specific markers, validates several populations by in situ hybridization, and finds a Ccl4+ microglial subset in mouse lesions and human multiple sclerosis lesions.

Key findings

Across all ages and conditions, clustering revealed nine unique microglial states, with cluster sizes ranging from 0.2% to 24% of all microglia; canonical microglial genes were not uniformly expressed, as only C1qa, Fcrls, and Trem2 were expressed in all clusters.
Microglial diversity was greatest at E14.5 and P5 and lower at P30 and P100; aging and injury redistributed states, including increases in Clusters 8 and 9. In aged P540 versus P100 mice, there were 2–4 times more microglia in aging-enriched Clusters OA2 and OA3, with OA2 expressing inflammatory genes such as Ccl4, Ccl3, and Il1b and OA3 expressing interferon-response genes including Ifitm3, Rtp4, and Oasl2.
In LPC-induced demyelination at 7 days post-lesion, injury-responsive Cluster IR2 was almost entirely composed of lesion microglia and subclustered into IR2.1–2.4; IR2.2 upregulated Cxcl10, and IR2.2/IR2.3 upregulated Ccl4. IRM shared a 12-gene core signature with disease-associated microglia (DAM), including Spp1, Lpl, and Apoe, but also had unique interferon-response genes.
Sex had almost no effect on microglial diversity or cluster proportions across E14.5, P4/P5, and P100; the only observed difference was female enrichment of the small Cluster Sx6 (~0.5% of microglia, observed only at P4/P5, enriched for Cd74, Ccl24, and Arg1). In human MS lesions, approximately 30% of microglia in the lesion were Ccl4+.

Methods

Microglia were FACS-purified from C57BL/6J mice at E14.5, P4/P5, P30, P100, and P540, plus adult P100 mice after focal LPC-induced demyelination at 7 days post-lesion; at least three to four biological replicates per age were collected, totaling 76,149 sequenced microglia from 41 animals.
Cells were processed with a droplet-based RNA-seq approach (10× Genomics Chromium), sequenced to ~40,000–60,000 reads/cell, and analyzed using an independent component analysis (ICA)-based clustering pipeline, including subclustering and canonical correlation analysis (CCA) for comparison with published DAM data.
Findings were validated with single-molecule fluorescent in situ hybridization (smFISH), chromogenic in situ hybridization, and immunohistochemistry in mouse tissue, and with human MS tissue from the UK MS Tissue Bank; statistical analyses included ANOVA with Tukey’s post hoc tests, t-tests, and gene-marker thresholds of >1.5 fold change and P < 1E-4 with Benjamini–Hochberg correction.

Limitations

Stated: further analysis is needed to establish whether the identified states are transient or represent terminal differentiation; lineage tracing is needed to determine the origin of Cluster 6 microglia and whether they give rise to mature microglia; manipulation of aged inflammatory microglia is needed to test whether they contribute to age-related brain inflammation; the small female-enriched Cluster Sx6 requires further validation; and whether other mouse lesion-enriched genes translate to human microglia needs confirmation.
Evident: the main dataset is mouse-based, and the injury analysis focuses on a single model (LPC-induced demyelination) at one time point (7 days post-lesion); human MS validation was limited to five control/patient samples and centered on Ccl4/Tmem119 staining.

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Crossref · 10.1101/406140

Cites

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It may state two separate claims as one. 65
Probably not a substantial claim. 31

In the paper
“For both rounds of analysis, independent components that captured batch or replicate effects were removed before clustering analysis (Fig S2d), as previously described (Saunders et al., 2018).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Results: > Isolation of microglia to minimize ex vivo activation
What the sources say
- Not checked yetcites Saunders et al., 2018 source
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Probably not a substantial claim.
In the paper
“suggests that this small subpopulation of microglia contributes to age-related brain inflammation; however manipulation of these microglia will be essential for testing this hypothesis.”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Results: > Small populations of inflammatory and interferon-responsive microglia emerge in the aged brain
What the sources say
- Not checked yetcites Franceschi et al., 2007 source
Load-bearingStrength:hedged· not yet calibratedCausal:conditional· not yet calibrated
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Probably not a substantial claim. The authors may not put it forward as true.
In the paper
“since its expression is maintained by resident human microglia in MS lesions and is not expressed by infiltrating immune cells (Zrzavy et al., 2017).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Results: > Diverse microglial activation responses are triggered in demyelinated mouse lesions and human MS tissue
What the sources say
- Not checked yetcites Zrzavy et al., 2017 source
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It may state two separate claims as one.
In the paper
“Another major class of activated microglia called Disease Associated Microglia (DAM) were recently identified in a mouse model of Alzheimer’s disease (5xFAD) (Keren-Shaul et al., 2017).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Results: > Diverse microglial activation responses are triggered in demyelinated mouse lesions and human MS tissue
What the sources say
- Not checked yetcites Keren-Shaul et al., 2017 source
Load-bearingStrength:plain· not yet calibrated
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“blocking TGF-beta signaling (which helps to confer microglia identity, (Butovsky et al., 2014)) has no major effect on microglia cell number, but causes a drastic shift in their gene expression including widespread upregulation of (or failure to downregulate) genes found in Cluster 6 microglia and in brain border macrophages, including Mrc1 (Wong et al., 2017).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Butovsky et al., 2014 source
- Not checked yetcites Wong et al., 2017 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
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It may state two separate claims as one.
In the paper
“microglia become activated and aberrantly remove synapses in the early stages of pathology in mouse models of Alzheimer’s disease, well before cognitive decline and plaque formation (Hong et al., 2016).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Hong et al., 2016 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“evidence of aberrant microglia activation has been found in many forms of neurodevelopmental and neurodegenerative disease, but the diversity of these responses and specificity of the microglia response to each disease needs further exploration (Salter and Stevens, 2017).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Salter and Stevens, 2017
Load-bearingStrength:plain· not yet calibratedCausal:correlational· not yet calibrated
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Current PET imaging ligands, including TSPO, are not selective for microglia and are better markers of neuroinflammation (Politis et al., 2012).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Politis et al., 2012 source
Load-bearingStrength:plain· not yet calibrated
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It may state two separate claims as one.
In the paper
“recent transplantation experiments suggest that Ms4a7 and other markers in Cluster 6 are specific to hematopoietic derived cells versus those derived from yolk-sac progenitors (Bennett et al., 2018).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Bennett et al., 2018 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Ccl4 antibody specificity was tested using secondary antibody only controls as well as with antibody preadsorption using recombinant Ccl4 protein, as previously described (Sekar et al., 2016).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > STAR Methods > METHOD DETAILS
What the sources say
- Not checked yetcites Sekar et al., 2016 source
Strength:plain· not yet calibrated
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Another group showed that these microglia were the predominant source of Igf1 in the early postnatal brain, and Igf1 conditional knockout in microglia affected the health of developing cortical neurons at the same age (Ueno et al., 2013).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Ueno et al., 2013 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Metabolic state is directly manipulated by cytokine and pattern-recognition receptors, and elevated glycolytic activity has been tied to immune cell activation (Everts et al., 2014; O’Neill and Pearce, 2016).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Everts et al., 2014 source
- Not checked yetcites O’Neill and Pearce, 2016
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The RNAscope® 2.5 HD Duplex Detection Kit (Chromogenic) was used in experiments involving 18 month-old mice to avoid autofluorescence from lipofuscin accumulation in the aged brain (Xu et al., 2008).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > STAR Methods > QUANTIFICATION AND STATISTICAL ANALYSIS
What the sources say
- Not checked yetcites Xu et al., 2008
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Many of the signals expressed in this subpopulation can be highly damaging to the brain. For example, Il1b and Tnf can both cause neurotoxicity (Takeuchi et al., 2006; Ye et al., 2013), and infiltrating immune cells attracted by the chemokines expressed in the Ccl4+ subpopulation can exacerbate pathology (Gadani et al., 2015).”
§ Single cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes > Discussion
What the sources say
- Not checked yetcites Takeuchi et al., 2006 source
- Not checked yetcites Ye et al., 2013
- Not checked yetcites Gadani et al., 2015 source
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86 of 86

The paper relies on this without support.
Microglia rapidly change states in response to their environment.
“Microglia, the resident immune cells of the brain, rapidly change states in response to their environment”
The paper relies on this without support.
There is a lack of molecular and functional signatures of different microglial populations.
“but we lack molecular and functional signatures of different microglial populations”
The paper relies on this without support.
Microglia have historically been characterized as resting, M1, or M2 based on simple in vitro stimulation methods.
“microglia have historically been characterized as ‘resting’, ‘M1’ (proinflammatory), or ‘M2’ (anti-inflammatory) - based on simple in vitro stimulation methods.”
The paper relies on this without support.
It is still unclear when microglia diverge from brain border neighbors and how quickly they differentiate.
“However, it is still unclear when microglia diverge from their brain border neighbors and how quickly they differentiate.”
The paper relies on this without support.
It is not until microglia infiltrate the brain parenchyma and are exposed to brain-derived signals that they achieve their unique identity.
“It is not until microglia infiltrate the brain parenchyma and are exposed to brain-derived signals that they achieve their unique identity.”
The paper relies on this without support.
The extent of the microglial response to aging has not been comprehensively studied, and it remains unclear how, where, and to what extent microglia change with normal aging.
“However, the extent of the microglial response to aging has not been comprehensively studied, and it remains unclear how, where (in the brain), and to what extent microglia change with normal aging.”
The paper relies on this without support.
It is unclear whether microglia tailor their responses to specific injury types or whether distinct microglial populations exist in pathological tissue.
“However, it is still unclear whether or how microglia tailor their response to specific injury types or whether distinct populations of microglia exist in pathological tissue, as we lack both the markers and tools to identify and characterize different activation states, should they exist.”
The paper relies on this without support.
Microglia respond robustly and rapidly to demyelination in the LPC model.
“third, microglia respond robustly and rapidly to demyelination in this model”
The paper relies on this without support.
Microglial activation is largely confined to the lesion where demyelination occurred.
“microglial activation is largely confined to the lesion where the demyelination has occurred.”
The paper relies on this without support.
At 7 days post-lesion, microglia are highly responsive and the lesion is transitioning from myelin debris cleanup to initial remyelination.
“We focused our analysis on 7 days post-lesion (7 dpl), a time point at which microglia are highly responsive and the lesion is undergoing a transition from myelin debris cleanup to the initial phases of remyelination (Fig 6a).”
The paper relies on this without support.
Demyelinated lesions contain a high density of activated microglia, generally in the core, where they can remove myelin debris and release factors into the lesion microenvironment.
“Demyelinated lesions contain a high density of activated microglia, generally in the core, where they can remove myelin debris and release factors into the lesion microenvironment.”
The paper relies on this without support.
In MS, infiltrating immune cells specifically target myelin and cause white matter lesions.
“In MS, infiltrating immune cells specifically target myelin and cause white matter lesions.”
The paper relies on this without support.
Microglia migrate, grow, and proliferate in response to injury.
“Because microglia migrate, grow, and proliferate in response to injury”

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Authors: Hammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., Macosko, E., Franklin, R. J. M., Piao, X., McCarroll, S., & Stevens, B.
Affiliations: Broad Institute (US)
Boston Children's Hospital (US)
Wellcome/MRC Cambridge Stem Cell Institute (GB)
Corresponding author: Stevens, Beth
ORCID: Hammond, Timothy R.
Dufort, Connor
Giera, Stefanie
Walker, Alec J.
Segel, Michael
Saunders, Arpiar
Macosko, Evan
Franklin, Robin J. M.
Piao, Xianhua
Stevens, Beth
Venue: Immunity
Publisher: openRxiv
Published: 2018-08-31
Volume: 50
Issue: 1
Pages: 253-271.e6
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1101/406140
PMC: PMC6655561
OpenAlex: W2901838561
Cited by: 2,225
References: 83
Citations by year: 2026: 257 · 2025: 312 · 2024: 304 · 2023: 343 · 2022: 351 · 2021: 308 · 2020: 218 · 2019: 123 · 2018: 4
FWCI: 72.90
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Immunity (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Apollo (University of Cambridge) (submittedVersion)
Apollo
Funders: Howard Hughes Medical Institute
Simons Foundation
International Rett Syndrome Foundation
Simons Foundation Autism Research Initiative
Rosetrees Trust
Lundbeckfonden (R182-2014-2844)
Stanley Center for Psychiatric Research, Broad Institute
Medical Research Council (MC_PC_12009)
National Institute of Mental Health (P50MH112491)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Keywords: microglia, microglial heterogeneity, microglial states, brain aging, brain injury, multiple sclerosis, reactive microglia, microglial development, single-cell RNA sequencing
MeSH terms: Adaptation, Physiological, Aging, Animals, Brain, Brain Injuries, Cell Differentiation, Demyelinating Diseases, Humans, Longevity, Mice, Inbred C57BL, Multiple Sclerosis, Sequence Analysis, RNA, Microglia, Mice, Single-Cell Analysis

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A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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Complex cell-state changes revealed by single cell RNA sequencing of 76,149 microglia throughout the mouse lifespan and in the injured brain

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