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.

Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart

“…Consistent with previous reports, we demonstrate that neonatal mice have a remarkable ability to recover cardiac function, whereas adult mice have a significantly limited capacity (10)(11)(12)(13)(14). The precise macrophage characterization and lineage tracing studies performed herein show that the injured neonatal heart contains an embryonic-derived lineage of cardiac macrophages that promote cardiomyocyte proliferation and coronary angiogenesis, but produce minimal inflammation.…”

“…Here, we extend these observations and underscore the emerging concept that distinct macrophage lineages exist within tissues and have different biological roles in maintaining homeostasis, consistent with Ilya Metchnikoff's empirically derived concept of "physiologic inflammation" originally proposed in 1901 (21). The concept that distinct macrophage subsets and lineages populate the injured neonatal and adult heart provides a mechanistic basis to explain why the neonatal and adult heart demonstrate different responses to injury and is consistent with and expands on the findings of Aurora and colleagues (14), who demonstrated that cardiac regeneration in the neonatal heart after myocardial infarction was dependent on macrophages. Furthermore, Aurora and colleagues demonstrate that macrophages isolated from infarcted neonatal hearts express a M2 gene expression profile, whereas macrophages isolated from infarcted P14 hearts display a M1 gene expression profile (14).…”

“…The concept that distinct macrophage subsets and lineages populate the injured neonatal and adult heart provides a mechanistic basis to explain why the neonatal and adult heart demonstrate different responses to injury and is consistent with and expands on the findings of Aurora and colleagues (14), who demonstrated that cardiac regeneration in the neonatal heart after myocardial infarction was dependent on macrophages. Furthermore, Aurora and colleagues demonstrate that macrophages isolated from infarcted neonatal hearts express a M2 gene expression profile, whereas macrophages isolated from infarcted P14 hearts display a M1 gene expression profile (14). One potential explanation for these intriguing observations is that distinct macrophage subsets and lineages are found in the infarcted neonatal and P14 heart.…”

“…After surgical apical resection, cryoablation, or myocardial infarction, neonatal mice efficiently regenerate myocardium (10-13), a process that is dependent on macrophages (14). The precise identity of neonatal macrophages and their relationship to macrophages found in the adult heart is unknown.…”

Distinct phenotypic features of neonatal murine macrophages

“…However, these studies are based on peripheral blood monocytes or CBMs, which further differentiate into macrophages ex vivo. Little is known about tissue macrophages in neonates, due to technical difficulties of their isolation and evaluation, but a recent study demonstrated their unique function during heart tissue regeneration [10].It has been shown that the heterogeneous murine macrophage populations are originating from distinct myeloid lineages. In light of these studies, data obtained from circulating mononuclear phagocytes, CBM or bone marrow derived macrophages might not be representative for tissue macrophages, especially in the neonatal period [5,11,12].…”