Systemic mesenchymal stem cell-derived exosomes reduce myocardial infarct size: characterization with MRI in a porcine model

Background Mesenchymal stem cells (MSCs) have been shown to exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes. Purpose To determine whether MSC-derived exosomes administered systemically by the convenient method of intravenous (IV) bolus injection reduce infarct size and improve cardiac function in an established porcine model of myocardial infarction (MI). Methods A total of 20 pigs underwent experimental MI by permanent ligation of the left circumflex coronary artery (LCX). Ten pigs (exosome treated) received twice daily IV injection of exosomes (1000ug protein equivalent) for 7 days. The remaining 10 pigs received vehicle control injections. Cardiac structure and function were measured by MRI which was performed at baseline (pre-MI) and repeated on days 7 and 28 post-MI. Infarct size was also confirmed post-mortem. Blood samples were drawn over first 7 days for measurement of hs Troponin T. The study followed the principles of laboratory animal care and was approved by our institution's IACUC. Results All LCX ligations resulted in permanent ischaemia with MI as evidenced by pallor of the myocardium, ECG changes including ST segment elevation and increases in plasma hs Troponin T. Exosomes administered IV for 7 days resulted in clear reduction (30–40%) of infarct size measured at both 7 (p<0.05) and 28 days (p<0.01) post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning (p<0.01) in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening (p<0.01) compared with control. However, global measures of LV function were less protected by exosome treatment. It is possible that greater preservation of global LV function may have been attenuated by increased cardiac fibrosis, as T1 values showed significant increase in the exosome pigs compared to control particularly in the infarct related segments. Conclusion Taken together, our results show clear effects of IV exosomes administered over 7 days to reduce infarct size with relatively preserved cardiac function compared to control treated infarct pigs. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): STaR Award (AM Richards), National Medical Research Council, Singapore. IAF-ICP, National Research Foundation, Singapore (RC Lai and SK Lim).