Macrophages are involved in every cardiovascular disease and are an attractive therapeutic target. Macrophage activation is complex and can be either beneficial or deleterious, depending upon its mode of action, its timing, and its duration. An important macrophage characteristic is its plasticity, which enables it to switch from one subset to another. Macrophages, which regulate healing and repair after myocardial infarction, have become a major target for both treatment and diagnosis (theranostic). The aim of the present review is to describe the recent discoveries related to targeting and modulating of macrophage function to improve infarct repair. We will briefly review macrophage polarization, plasticity, heterogeneity, their role in infarct repair, regeneration, and cross talk with mesenchymal cells. Particularly, we will focus on the potential of macrophage targeting in situ by liposomes. The ability to modulate macrophage function could delineate pathways to reactivate the endogenous programs of myocardial regeneration. This will eventually lead to development of small molecules or biologics to enhance the endogenous programs of regeneration and repair.

BackgroundMacrophages and Wnt proteins (Wnts) are independently involved in cardiac development, response to cardiac injury, and repair. However, the role of macrophage‐derived Wnts in the healing and repair of myocardial infarction (MI) is unknown. We sought to determine the role of macrophage Wnts in infarct repair.Methods and ResultsWe show that the Wnt pathway is activated after MI in mice. Furthermore, we demonstrate that isolated infarct macrophages express distinct Wnt pathway components and are a source of noncanonical Wnts after MI. To determine the effect of macrophage Wnts on cardiac repair, we evaluated mice lacking the essential Wnt transporter Wntless (Wls) in myeloid cells. Significantly, Wntless‐deficient macrophages presented a unique subset of M2‐like macrophages with anti‐inflammatory, reparative, and angiogenic properties. Serial echocardiography studies revealed that mice lacking macrophage Wnt secretion showed improved function and less remodeling 30 days after MI. Finally, mice lacking macrophage‐Wntless had increased vascularization near the infarct site compared with controls.ConclusionsMacrophage‐derived Wnts are implicated in adverse cardiac remodeling and dysfunction after MI. Together, macrophage Wnts could be a new therapeutic target to improve infarct healing and repair.

The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by .