[HTML][HTML] Macrophages are required for neonatal heart regeneration

AB Aurora, ER Porrello, W Tan… - The Journal of …, 2014 - Am Soc Clin Investig
AB Aurora, ER Porrello, W Tan, AI Mahmoud, JA Hill, R Bassel-Duby, HA Sadek, EN Olson
The Journal of clinical investigation, 2014Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation