Invited commentary

Abstract

In their article entitled “Recruitment and therapeutic application of macrophages in skeletal muscles after hind limb ischemia,” Dr Hsieh and colleagues performed a study designed to analyze the kinetics of recruitment of myeloid cells to ischemic muscle. This study is particularly important in light of recent clinical trials for cell-based therapy for limb ischemia demonstrating that bone marrow-derived mononuclear cells can improve capillary density after intramuscular delivery.1Raval Z. Losordo D.W. Cell therapy of peripheral arterial disease: from experimental findings to clinical trials.Circ Res. 2013; 112: 1288-1302Crossref PubMed Scopus (175) Google Scholar The evaluation of myeloid cells as therapy for critical limb ischemia is a relatively new direction as the majority of clinical trials done previously have focused on nonmyeloid stem cells and have paid little attention to the timing of cell transplantation. This group attempts to tackle a challenging question related to the timing of recruitment of macrophage populations after ischemic injury to maximize the therapeutic effects. In short, this study used a femoral artery excision model whereby ischemia was induced and followed by injection of bone marrow-derived macrophages 24 hours later. The outcomes measured included blood flow and functional outcomes of the ischemic muscle. As expected, the authors found that delivering “M2” or anti-inflammatory macrophages in the early or acute inflammatory phase does not allow progression of normal inflammation, interferes with regeneration, and impedes normal tissue formation. It is well known that repair of injury is dependent on progression through distinct overlapping phases; however, the failure of these phases to occur in timely progressive fashion will promote disease. The macrophage is a particularly important cell in this process because of its dynamic plasticity that allows the cell to have both tissue destructive and reparative properties. Thus, this paper examines a phenomenon well borne out in other tissues, in which excessive proinflammatory monocytes-macrophages at later time points may prolong inflammation and decrease muscle repair; however, anti-inflammatory macrophages delivered early after injury cause persistent fibrosis, which also hastens muscle repair. Hence, with respect to myeloid cell-based therapies, timing after injury is of critical importance. The ability to control initiation and resolution of inflammation by mediating macrophage phenotype will be critical for advancing these therapies. What remains lacking in this work is the translational component, demonstrating that these macrophages enhance angiogenesis and reduce limb loss. However, this work is an important initial step toward translation and may help improve cell-based therapy for limb ischemia. The opinions or views expressed in this commentary are those of the authors and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery. Recruitment and therapeutic application of macrophages in skeletal muscles after hind limb ischemiaJournal of Vascular SurgeryVol. 67Issue 6PreviewPeripheral arterial disease can cause not only ischemia but also skeletal muscle damage. It has been known that macrophages (MPs) play an important role in coordinating muscle repair; however, phenotype transition of monocyte-MP in ischemic muscle has not been well defined. Hence, the purpose of this study was to examine the temporal recruitment of MPs and to explore their therapeutic effect on ischemic muscle regeneration. Full-Text PDF Open Archive