Journal Article

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Clemente-Casares, Xavier, Zaman, Rysa, Robbins, Clinton S., Epelman, Slava, Dick, Sarah A., Husain, Mansoor, Aronoff, Laura, Althagafi, Marwan G., Hosseinzadeh, Siyavash, Kantores, Crystal, Razani, Babak, Wong, Anthony, Barbu, Iulia, Nejat, Sara, Chen, Jinmiao, Besla, Rickvinder, Ginhoux, Florent, Lavine, Kory J., Macklin, Jillian A., Momen, Abdul, Cybulsky, Myron I.

2019

Overview

Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4 + LYVE1 + MHC-II lo CCR2 − resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes partially replaced resident TIMD4 – LYVE1 – MHC-II hi CCR2 − macrophages and fully replaced TIMD4 − LYVE1 − MHC-II hi CCR2 + macrophages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4 + and TIMD4 – resident macrophage abundance, whereas CCR2 + monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate mapping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1 -based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages. Epelman and colleagues use fate mapping and single-cell transcriptomics to describe the dynamics of resident and recruited cardiac macrophages during ischemic injury.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2504/342 / 631/250/256/2516 / Animals / Biomedical and Life Sciences / Biomedicine / CCR2 protein / Cell Differentiation / Cell fate / Cell Lineage / Cell Self Renewal / CX3C Chemokine Receptor 1 - metabolism / CX3CR1 protein / Fate maps / Gene expression / Gene Expression Profiling / Genetic aspects / Heart / Heart attack / Heart attacks / Histocompatibility Antigens Class II - metabolism / Immunology / Infectious Diseases / Ischemia / Macrophages / Macrophages - physiology / Major histocompatibility complex / Membrane Proteins - metabolism / Mice / Mice, Transgenic / Monocyte chemoattractant protein 1 / Monocytes / Myocardial infarction / Myocardial Infarction - immunology / Myocardium - pathology / Parabiosis / Receptors, CCR2 - genetics / Receptors, CCR2 - metabolism / RNA sequencing / Single-Cell Analysis / Ventricular Remodeling / Vesicular Transport Proteins - metabolism