Fate-mapping infiltrating monocytes following experimental myocardial infarction reveals differentiation trajectories in the infarcted heart
4 affiliations
- 1Center for Cardiovascular Research, Division of Cardiology, Department of Medicine,
- 2Department of Surgery,
- 3Department of Pathology and Immunology, and
- 4Department of Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, USA
Abstract
Inflammation contributes to the pathogenesis of myocardial infarction and heart failure and represents a viable therapeutic target. Monocytes and their progeny are highly abundant and display striking functional diversity, serving as key determinants of myocardial inflammation and tissue repair. Much remains to be learned regarding mechanisms and signaling events that instruct monocyte fate decisions. We devised a genetic lineage tracing strategy using Ccr2crERT2Rosa26LSL-tdTomato mice in combination with single cell RNA-seq to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes were recruited to the heart early after injury and gave rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that were specified prior to extravasation and chronically persisted within the myocardium. Pseudotime analysis predicted 2 differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we demonstrated that macrophages expressing a type I interferon-responsive signature were an intermediate population that gave rise to MHC-IIhi macrophages, were localized within the border zone, induce regulatory T cells, and promote myocardial protection. Collectively, these data uncover complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.
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BibTeX
@article{koenig2026fatemapping,
title = {{Fate-mapping infiltrating monocytes following experimental myocardial infarction reveals differentiation trajectories in the infarcted heart}},
author = {Andrew L. Koenig and Farid F. Kadyrov and Junedh Amrute and Steven Yang and Carla J. Weinheimer and Jessica M. Nigro and Attila Kovacs and Wenjun Li and Gabriella B. Smith and Lance Yeh and Daniel Kreisel and Kory J. Lavine},
journal = {Journal of Clinical Investigation},
year = {2026},
month = jul,
doi = {10.1172/jci189684},
url = {https://doi.org/10.1172/jci189684},
note = {CC BY},
}
RIS
TY - JOUR
TI - Fate-mapping infiltrating monocytes following experimental myocardial infarction reveals differentiation trajectories in the infarcted heart
AU - Andrew L. Koenig
AU - Farid F. Kadyrov
AU - Junedh Amrute
AU - Steven Yang
AU - Carla J. Weinheimer
AU - Jessica M. Nigro
AU - Attila Kovacs
AU - Wenjun Li
AU - Gabriella B. Smith
AU - Lance Yeh
AU - Daniel Kreisel
AU - Kory J. Lavine
PY - 2026
DA - 2026/07/07
JO - Journal of Clinical Investigation
DO - 10.1172/jci189684
UR - https://doi.org/10.1172/jci189684
AB - Inflammation contributes to the pathogenesis of myocardial infarction and heart failure and represents a viable therapeutic target. Monocytes and their progeny are highly abundant and display striking functional diversity, serving as key determinants of myocardial inflammation and tissue repair. Much remains to be learned regarding mechanisms and signaling events that instruct monocyte fate decisions. We devised a genetic lineage tracing strategy using Ccr2crERT2Rosa26LSL-tdTomato mice in combination with single cell RNA-seq to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes were recruited to the heart early after injury and gave rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that were specified prior to extravasation and chronically persisted within the myocardium. Pseudotime analysis predicted 2 differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we demonstrated that macrophages expressing a type I interferon-responsive signature were an intermediate population that gave rise to MHC-IIhi macrophages, were localized within the border zone, induce regulatory T cells, and promote myocardial protection. Collectively, these data uncover complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.
SN - 0021-9738
SN - 1558-8238
ER -