Genetic Mapping of Monocyte Fate Decisions Following Myocardial Infarction

Andrew L Koenig; Farid F Kadyrov; Junedh M Amrute; Steven Yang; Carla J Weinheimer; Jessica M Nigro; Attila Kovacs; Gabriella Smith; Kory J Lavine

doi:10.1101/2023.12.24.573263

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Genetic Mapping of Monocyte Fate Decisions Following Myocardial Infarction

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Genetic Mapping of Monocyte Fate Decisions Following Myocardial Infarction

Andrew L Koenig, Farid F Kadyrov, Junedh M Amrute, Steven Yang, Carla J Weinheimer, Jessica M Nigro, Attila Kovacs, Gabriella Smith and Kory J Lavine

bioRxiv

Cold Spring Harbor Laboratory, 1.2

02/04/2025

DOI: 10.1101/2023.12.24.573263

PMID: 39974922

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https://doi.org/10.1101/2023.12.24.573263View

Preprint (Author's original) This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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 incredible 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-sequencing to map the differentiation trajectories of monocytes that infiltrate the heart after reperfused myocardial infarction. Monocytes are recruited to the heart early after injury and give rise to transcriptionally distinct and spatially restricted macrophage and dendritic cell-like subsets that are specified prior to extravasation and chronically persist within the myocardium. Pseudotime analysis predicted two differentiation trajectories of monocyte-derived macrophages that are partitioned into the border and infarct zones, respectively. Among these trajectories, we show that macrophages expressing a type I IFN responsive signature are an intermediate population that gives rise to MHC-IIhi macrophages, are localized within the border zone, and promote myocardial protection. Collectively, these data uncover new complexities of monocyte differentiation in the infarcted heart and suggest that modulating monocyte fate decisions may have clinical implications.

Immunology

Details

Title: Subtitle: Genetic Mapping of Monocyte Fate Decisions Following Myocardial Infarction
Creators: Andrew L Koenig - Washington University in St. Louis
Farid F Kadyrov - Washington University in St. Louis
Junedh M Amrute - Washington University in St. Louis
Steven Yang - Washington University in St. Louis
Carla J Weinheimer - Washington University in St. Louis
Jessica M Nigro - Washington University in St. Louis
Attila Kovacs - Washington University in St. Louis
Gabriella Smith - Washington University in St. Louis
Kory J Lavine - Washington University in St. Louis
Resource Type: Preprint
Publication Details: bioRxiv
Edition: 1.2
DOI: 10.1101/2023.12.24.573263
PMID: 39974922
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory
Number of pages: 30
Language: English
Date posted: 02/04/2025
Academic Unit: Stead Family Department of Pediatrics
Record Identifier: 9985161456102771

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