Macrophages are required for neonatal heart regeneration
Arin B. Aurora, Enzo R. Porrello, Wei Tan, Ahmed I. Mahmoud, Joseph A. Hill, Rhonda Bassel-Duby, Hesham A. Sadek, Eric N. Olson
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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Research Article

Macrophages are required for neonatal heart regeneration

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 6

Angiogenesis is impaired in monocyte/macrophage-depleted neonates following MI.

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Angiogenesis is impaired in monocyte/macrophage-depleted neonates follow...
(A) Sections from control or Cl2MDP-L–treated hearts stained with PECAM (red) and Hoechst (blue) to label endothelial cells and nuclei, respectively, 7 days after MI. Vessels are visible in infarct areas (marked by dashed lines) in controls but not in the Cl2MDP-L group. Original magnification, ×10 (top row); ×20 (bottom row). (B–D) The vasculature was visualized by endomucin immunohistochemistry (brown) on serial heart sections starting below the ligature and progressing toward the apex of control and Cl2MDP-L–treated neonates at (B) 7 and (D) 21 days after MI. (B) Two serial heart sections for each mouse show newly forming vessels invading the IZ in control but not Cl2MDP-L–treated neonates, and lines indicate area used to quantify vessel density. (C) Significantly fewer neovessels are present in Cl2MDP-L–treated mice compared with controls. Data are mean ± SEM. ****P < 0.0001. (D) At 21 days after MI, control mice have new myocardia that contain abundant endomucin-positive vasculature, while heart sections from Cl2MDP-L–treated mice contain areas devoid of new vessels. Lines indicate area lacking vessels. Scale bars: 1 mm (top rows); 200 μm (bottom rows).