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

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 1

Mononuclear phagocytes respond differently to MI in P1 and P14 mice.

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Mononuclear phagocytes respond differently to MI in P1 and P14 mice. (A)...
(A) Single cell suspensions isolated from hearts of mice before MI (Pre) or 7 days following MI at P1 or P14 were stained with anti-CD11b, –Ly-6G, –Ly-6C, -F4/80, -CD11c, –I-Ab mAbs and analyzed by FACS. Mononuclear phagocytes were identified as CD11b+Ly-6G– and neutrophils were identified as CD11b+Ly-6G+ (top panels). Within the mononuclear phagocyte population, macrophages/DCs are classified as (F4/80/CD11c/I-Ab)hiLy-6Clo and monocytes are depicted as (F4/80/CD11c/I-Ab)loLy-6Chi or (F4/80/CD11c/I-Ab)loLy-6Clo (bottom panels). Percentages of cells are indicated for the representative dot plots. (B) Quantification at the indicated time points to compare the percentage of all mononuclear phagocytes or macrophages/DCs (MΦ/DCs) relative to the leukocyte-enriched gate or mononuclear phagocyte population, respectively, in mice undergoing MI at P1 (blue) or P14 (red) (n = 3–5 per time point). (C) Total number of mononuclear phagocytes per milligram of heart tissue 7 days after MI at P1 or P14. (D) Relative percentages of Ly-6Chi and Ly-6Clo monocytes in the heart were quantified over time following MI of mice at P1 or P14 (n = 3–5 per time point). (E) Real-time RT-PCR analysis of cardiac chemokine expression at 3 days following MI of P1 or P14 mice. Expression is relative to that in P1 sham-operated mice [P1 Sham]) (n = 3). Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.