Blunting Half of the Double-Edged Sword

Abstract

See related article, pages 1280–1289 During a myocardial infarction (MI), tissue damage resulting from the ischemia and subsequent reperfusion injury triggers a complex combination of cellular responses,1 much of which is bone marrow–derived. Some of these responses involve a harmful inflammatory reaction to cytokines released by dying cardiomyocytes that can exacerbate the ongoing local structural damage. Other responses are beneficial, for example, the prohealing arm of the inflammatory response that replaces the necrotic and inflamed region with a fibrous scar. Still other beneficial effects are thought to be mediated by mobilized bone marrow cells (BMCs) of multiple lineages that aid in tissue healing.2,3 Much effort has gone into harnessing this endogenous cellular response by harvesting resident or mobilized bone marrow–derived cells and administering them to post-MI hearts,4–7 with the hope that the cells will regenerate myocardium via differentiation2,8 or will preserve at-risk myocardium by actively9 or passively10 releasing paracrine growth factors or secreting exosomes.11,12 However, the aforementioned inflammatory response can cause problems by creating an environment in the post-MI heart that may be inhospitable for naturally attracted and therapeutically administered BMCs alike. Moreover, the MI-induced inflammatory response transitions the BMCs themselves to a more proinflammatory state, interfering with their therapeutic abilities.13 In this issue of Circulation Research , Krishnamurthy and colleagues14 explore naturally occurring mechanisms of dampening the inflammatory response that could potentially augment the efficacy of cell therapy for MI. Their focus is on a particular subpopulation of BMCs, the endothelial progenitor cells (EPCs). These cells, which were originally discovered in rodents, …