title: Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart.
abstract: The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: Organs are replete with resident macrophages of embryonic origin distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonic-derived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine.
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine.
authors.forename: Slava
authors.initials: S
authors.lastname: Epelman
authors.affiliation: Center for Membrane Excitability, Department of Cell Biology and Physiology.
authors.forename: Keita
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Diabetic Cardiovascular Disease Center, Division of Cardiology, Department of Medicine.
authors.forename: Kassandra J
authors.initials: KJ
authors.lastname: Weber
authors.affiliation: Center for Membrane Excitability, Department of Cell Biology and Physiology.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Nichols
authors.affiliation: Diabetic Cardiovascular Disease Center, Division of Cardiology, Department of Medicine.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Schilling
authors.affiliation: Department of Developmental Biology, and.
authors.forename: David M
authors.initials: DM
authors.lastname: Ornitz
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
authors.affiliation: Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, DMANN@dom.wustl.edu.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Mann
mesh_terms: D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000628:therapy; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000637:transplantation; D020127:Recovery of Function; D012038:Regeneration; D020257:Ventricular Remodeling
keywords: cardiac repair; inflammation; macrophages