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Macrophages are required for neonatal heart regeneration
Arin B. Aurora, … , Hesham A. Sadek, Eric N. Olson
Arin B. Aurora, … , Hesham A. Sadek, Eric N. Olson
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(3):1382-1392. https://doi.org/10.1172/JCI72181.
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Research Article Article has an altmetric score of 32

Macrophages are required for neonatal heart regeneration

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Abstract

Myocardial infarction (MI) leads to cardiomyocyte death, which triggers an immune response that clears debris and restores tissue integrity. In the adult heart, the immune system facilitates scar formation, which repairs the damaged myocardium but compromises cardiac function. In neonatal mice, the heart can regenerate fully without scarring following MI; however, this regenerative capacity is lost by P7. The signals that govern neonatal heart regeneration are unknown. By comparing the immune response to MI in mice at P1 and P14, we identified differences in the magnitude and kinetics of monocyte and macrophage responses to injury. Using a cell-depletion model, we determined that heart regeneration and neoangiogenesis following MI depends on neonatal macrophages. Neonates depleted of macrophages were unable to regenerate myocardia and formed fibrotic scars, resulting in reduced cardiac function and angiogenesis. Immunophenotyping and gene expression profiling of cardiac macrophages from regenerating and nonregenerating hearts indicated that regenerative macrophages have a unique polarization phenotype and secrete numerous soluble factors that may facilitate the formation of new myocardium. Our findings suggest that macrophages provide necessary signals to drive angiogenesis and regeneration of the neonatal mouse heart. Modulating inflammation may provide a key therapeutic strategy to support heart regeneration.

Authors

Arin B. Aurora, Enzo R. Porrello, Wei Tan, Ahmed I. Mahmoud, Joseph A. Hill, Rhonda Bassel-Duby, Hesham A. Sadek, Eric N. Olson

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Figure 3

Depletion of monocytes/macrophages in a model of neonatal heart regeneration.

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Depletion of monocytes/macrophages in a model of neonatal heart regenera...
(A) Experimental strategy to deplete monocytes/macrophages using clodronate liposomes (Cl2MDP-L) following MI at P1. (B) Spleens harvested from control or monocyte/macrophage-depleted mice 3 days following sham or MI surgeries are shown. Scale bar: 4 mm. (C) Contour plots from mice 3 days after MI depict mononuclear phagocyte and neutrophil percentages and numbers in hearts after depleting with Cl2MDP-L or injection of saline (control). (D) Mononuclear phagocytes were further specified as Ly-6Chi monocytes (bottom right), Ly-6Clo monocytes (bottom left), and macrophages/DCs (top left). (E) By 7 days after MI, spleens weigh significantly less in Cl2MDP-L–treated neonates compared with those in control mice. Data represent mean ± SEM. ***P < 0.0001. (F) H&E-stained sections of the spleen and immunohistochemistry with F4/80 show that Cl2MDP-L–treated mice have been depleted of monocytes/macrophages 7 days following MI. Scale bar: 40 μm. (G) Immunohistochemical staining for Mac-3 depicts monocyte/macrophage depletion in the IZ of heart sections from Cl2MDP-L–treated mice compared to control mice. Scale bar: 40 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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