Dynamics of monocyte-derived macrophage diversity in experimental myocardial infarction
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Abstract
Aims: Macrophages have a critical and dual role in post-ischaemic cardiac repair, as they can foster both tissue healing and damage. Multiple subsets of tissue resident and monocyte-derived macrophages coexist in the infarcted heart, but their precise identity, temporal dynamics, and the mechanisms regulating their acquisition of discrete states are not fully understood. To address this, we used multi-modal single-cell immune profiling, combined with targeted cell depletion and macrophage fate mapping, to precisely map monocyte/macrophage transitions after experimental myocardial infarction. Methods and results: We performed single-cell transcriptomic and cell-surface marker profiling of circulating and cardiac immune cells in mice challenged with acute myocardial infarction, and integrated single-cell transcriptomes obtained before and at 1, 3, 5, 7, and 11 days after infarction. Using complementary strategies of CCR2+ monocyte depletion and fate mapping of tissue resident macrophages, we determined the origin of cardiac macrophage populations. The macrophage landscape of the infarcted heart was dominated by monocyte-derived cells comprising two pro-inflammatory populations defined as Isg15hi and MHCII+Il1b+, alongside non-inflammatory Trem2hi cells. Trem2hi macrophages were observed in the ischaemic area, but not in the remote viable myocardium, and comprised two subpopulations sequentially populating the heart defined as Trem2hiSpp1hi monocyte-to-macrophage intermediates, and fully differentiated Trem2hiGdf15hi macrophages. Cardiac Trem2hi macrophages showed similarities to ‘lipid-associated macrophages’ found in mouse models of metabolic diseases and were observed in the human heart, indicating conserved features of this macrophage state across diseases and species. Ischaemic injury induced a shift of circulating Ly6Chi monocytes towards a Chil3hi state with granulocyte-like features, but the acquisition of the Trem2hi macrophage signature occurred in the ischaemic tissue. In vitro, macrophages acquired features of the Trem2hi signature following apoptotic-cell efferocytosis. Conclusion: Our work provides a comprehensive map of monocyte/macrophage transitions in the ischaemic heart, constituting a valuable resource for further investigating how these cells may be harnessed and modulated to promote post-ischaemic heart repair.
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Single-cell transcriptomics has revealed the presence of numerous subsets/states of macrophages in any given injured tissue in humans.
“The growing accessibility of single-cell transcriptomics has also revealed the presence of numerous subsets/states of macrophages in any given injured tissue in humans (30–33).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [32]
The Results section (‘Single-cell CITE-seq analysis of macrophages in the healthy and infarcted heart’; page unavailable) identifies multiple monocyte/macrophage populations in infarcted mouse hearts. A separate Results section (‘Trem2hi macrophage subsets have a LAM transcriptional signature conserved in humans’; page unavailable) reports a TREM2-enriched macrophage population in human ischaemic heart data. The paper does not establish numerous macrophage states in any given injured human tissue; its detailed multi-state analysis is in mice. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe LAM phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury as well as in macrophages surrounding the bile duct in the healthy liver.
“Interestingly, this phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury (32, 33, 38, 110–121) as well as in macrophages surrounding the bile duct in the healthy liver (62).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [32]
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ResultThe human heart contains distinct macrophage subsets with divergent origins and functions
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- Authors
- Rizzo, G., Gropper, J., Piollet, M., Vafadarnejad, E., Rizakou, A., Bandi, S. R., Arampatzi, P., Krammer, T., DiFabion, N., Dietrich, O., Arias-Loza, A.-P., Prinz, M., Mack, M., Schlepckow, K., Haass, C., Silvestre, J.-S., Zernecke, A., Saliba, A.-E., & Cochain, C.
- Affiliations
- Universitätsklinikum Würzburg (DE)
- Helmholtz Centre for Infection Research (DE)
- Comprehensive Heart Failure Center, University Hospital Würzburg , Am Schwarzenberg 15, A15, 97078 Würzburg , Germany
- University of Freiburg (DE)
- University Hospital Regensburg (DE)
- German Center for Neurodegenerative Diseases (DE)
- Inserm (FR)
- Corresponding author
- Cochain, Clément
- ORCID
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-08-11
- Volume
- 119
- Issue
- 3
- Pages
- 772-785
- ISSN
- 0008-6363 (ISSN-L)
- 1755-3245
- PMC
- PMC10153424
- OpenAlex
- W4290997111
- Cited by
- 165
- References
- 17
- Citations by year
- 2026: 34 · 2025: 43 · 2024: 49 · 2023: 17 · 2022: 13 · 2021: 7 · 2020: 2
- FWCI
- 21.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cardiovascular Research (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- DZNE Pub (submittedVersion, cc-by-nc)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by-nc)
- Funders
- Interdisciplinary Center for Clinical Research
- University Hospital Würzburg
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- monocyte-derived macrophages, myocardial infarction, lipid-associated macrophages, ISG15, MHC class II, GDF15
- MeSH terms
- Animals, Humans, Macrophages, Mice, Inbred C57BL, Monocytes, Myocardial Infarction, Myocardium, Phagocytosis, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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