Abstract 19257: Mesenchymal Stem Cells Require CD73 Activity to Reduce Leukocyte Associated Inflammation Following Myocardial Ischemia-Reperfusion Injury
Introduction: Cell death following myocardial ischemia-reperfusion (MI/R) injury releases toxic metabolites in the interstitium, eliciting a potent immune response. Therapeutic use of MSCs represents a novel strategy to target this pathophysiologic cascade and reduce myocardial necrosis. This study examines whether early implantation of MSCs regulates excess inflammation following injury and investigates whether CD73 dependent conversion of immunogenic ATP/ADP to anti-inflammatory adenosine by MSCs represents a potential mechanism for their immuno-modulatory capacity in vivo.
Methods: Adult rats underwent 30 minutes of MI/R injury and were treated with saline, hydrogel encapsulated mesenchymal stem cells (eMSCs), or eMSCs pretreated with CD73 inhibitor (APCP-eMSC). Inflammation was measured from myocardium 1 day following injury. Quantification of H2O2 was performed by amplex red assay and enumeration of leukocyte infiltration by myocardial digestion and flow cytometry. Longitudinal cardiac function was measured by echocardiography.
Results: Infiltration of myocardium by CD45+ leukocytes was reduced in animals treated with eMSCs compared to saline; however, this effect was reversed by inhibition of CD73 with APCP (Figure 1). Cell subsets including MPO+ neutrophils and CD68+ macrophages were also reduced as a result of eMSC therapy (N=4, P<0.05). Myocardial H2O2 production was attenuated by eMSCs compared to saline (N=6, P<0.05). eMSCs improved cardiac function compared to saline control as early as 7 days following injury and persisted up to 28 days as determined by global longitudinal strain (N=6, P<0.05).
Conclusion: This is the first study to demonstrate that MSCs reduce ROS production in vivo and that MSC-CD73 activity is critical for cultivation of an anti-inflammatory microenvironment. Future studies to identify whether CD73 activity is necessary for inhibition of immune cell activity and subsequent cardio-protection will be pursued.
Author Disclosures: E. Shin: None. L. Wang: None. A. Garcia: None. R. Tirouvanziam: None. R. Levit: None.
- © 2016 by American Heart Association, Inc.