Loss of Macrophage Wnt Secretion Improves Remodeling and Function After Myocardial Infarction in Mice

Abstract

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 roles of Wnt/β‐catenin pathway in tissue development and regenerative medicine

“…PSCs including ESCs and iPSCs are the most important stem cells population with the greatest capacity for cardiac regeneration, mostly because of the distinguished potential to proliferative unlimitedly and differentiate into the main cardiovascular lineages (cardiomyocytes, smooth muscle, and endothelial cells) (Ozhan & Weidinger, ). As with its involvement in cardiac specification and development, the Wnt/β‐catenin pathway has been demonstrated by accumulating research groups to be contributed in proreparative and profibrotic response to cardiac ischemic injury (Bastakoty et al, ; Le Dour et al, ; Palevski et al, ). Seventy‐two hours after cardiac injury, the activation of Wnt/β‐catenin signaling pathway is observed in multiple cells of the heart (Aisagbonhi et al, ; Oerlemans et al, ).…”

Characterization of macrophages infiltrating peri‐implantitis lesions

“…Macrophages undergo polarization in response to environmental cues. Notably, M1 macrophages are involved in the pro-inflammatory response that can be caused by bacteria and its cues, while M2 macrophages play a role in the resolution of inflammation and tissue repair (Palevski et al, 2017;Yu et al, 2016). Macrophages are also responsible for the production and secretion of cytokines.…”

Beta‐catenin promotes macrophage‐mediated acute inflammatory response after myocardial infarction

“…Therefore, our future plan is to investigate cardiac macrophage activity and heart function in β‐catenin‐deficient mice after MI. Interestingly, a recent study reports that deletion of Wnt secretion in macrophages improves remodeling and function after MI . This study shows that Wnt‐deficient macrophages harbor an M2‐like subpopulation with reparative, angiogenic, and anti‐inflammatory features.…”

“…Interestingly, a recent study reports that deletion of Wnt secretion in macrophages improves remodeling and function after MI. 28 This study shows that Wnt-deficient macrophages harbor an M2-like subpopulation with reparative, angiogenic, and anti-inflammatory features. Although this study focuses on the effects of macrophage-derived Wnts rather than the effects of Wnt signaling on macrophage functions, it suggests that b-catenin-mediated signaling induce macrophage polarization toward the proinflammatory type, which is consistent with our findings.…”