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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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 4

Depletion of monocytes/macrophages blocks heart regeneration in neonatal mice.

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Depletion of monocytes/macrophages blocks heart regeneration in neonatal...
(A) At 7 days after MI, H&E-stained serial heart sections, starting below the ligature and progressing toward the apex (3 sections per heart), show a diminishing infarct area that has been displaced to the periphery in control mice. Cl2MDP-L–treated mice maintain an interstitial scar. The injured area is circled. Scale bar: 1 mm. (B) Masson’s trichrome staining of serial sections, starting below the ligature and progressing toward the apex, from control or Cl2MDP-L–treated mice 21 days following MI at P1 to visualize fibrosis. The injured area is circled. Scale bar: 1 mm. (C and D) Picrosirius red staining on heart sections from control or Cl2MDP-L–treated mice 21 days following MI at P1. (C) Representative images and (D) quantification as a percentage of total section area (≥7 sections per heart) show significantly more fibrosis in the Cl2MDP-L–treated group (n = 7–8 mice per group). Scale bar: 1 mm. (E) Cardiac function following MI or sham surgeries was assessed at 28 days after MI by echocardiography. Data are expressed as the percentage of FS (n = 3–4 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.01.