Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Abstract

Background During myocardial ischemia/reperfusion ( MI /R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP , which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells ( MSC s) are a potential treatment modality for MI /R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD 73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC ‐mediated conversion of AMP into adenosine reduces inflammation in early MI /R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery. Methods and Results Adult rats were subjected to 30 minutes of MI /R injury. MSC s were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSC s were pretreated with the CD 73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSC s increase myocardial adenosine availability following injury via CD 73 activity. MSC s also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC ‐mediated CD 73 activity. Finally, through echocardiography we found that CD 73 activity on MSC s was critical to optimal protection of cardiac function following MI /R injury. Conclusions MSC ‐mediated conversion of AMP to adenosine by CD 73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI /R injury.