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

• Type of Material: Article
• Authors: Eric Y. Shin, Emory University; Lanfang Wang Wang, Emory University; Marina Zemskova, Emory University; Juline Deppen, Emory University; Kai Xu, Emory University; Fred Strobel, Emory University; Andres J. Garcia, Georgia Institute of Technology; Rabindra M. Tirouvanziam, Emory University; Rebecca D. Levit, Emory University
• Language: English
• Date: 2018-01-23
• Publisher: Wiley Open Access: Creative Commons Attribution Non-Commercial
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/JAHA.117.006949
• Title of Journal or Parent Work: Journal of the American Heart Association
• ISSN: 2047-9980
• Volume: 7
• Issue: 2
• Start Page: e006949
• End Page: e006949
• Grant/Funding Information: This study was supported by American Heart Association Scientist Development Grant (14SDG18530001) to Levit, and by the National Heart, Lung, and Blood Institute of the NIH under award number T32HL007745 to Shin.
• Keywords: STEM-CELLS; NEUTROPHIL DEPLETION; A(1)/A(2A) RECEPTOR AGONIST; Cardiac & Cardiovascular Systems; ISCHEMIA-REPERFUSION INJURY; HEART-DISEASE; Life Sciences & Biomedicine; Cardiovascular System & Cardiology; VASCULAR SMOOTH-MUSCLE; TUMOR-GROWTH; INFARCT SIZE; cell therapy; cardioprotection; ischemia; Science & Technology; mesenchymal stem cell; CORONARY ANGIOPLASTY; A(2A) RECEPTOR; myocardial inflammation; ischemia reperfusion injury; inflammation
• Research Categories: Health Sciences, Medicine and Surgery; Chemistry, General

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 (MSCs) 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. CD73, an ecto-50-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. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, a,b-methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs 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 CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury. Conclusions--MSC-mediated conversion of AMP to adenosine by CD73 exerts a powerful anti-inflammatory effect critical for cardiac recovery following MI/R injury.