Systemic Mesenchymal Stem Cell-Derived Exosomes Reduce Myocardial Infarct Size: Characterization With MRI in a Porcine Model

Christopher J Charles, Renee R Li, Teresa Yeung, Stephane M Ibraham Mazlan, Ruenn Chai Lai, Dominique P V de Kleijn, Sai Kiang Lim, A Mark Richards, Christopher J Charles, Renee R Li, Teresa Yeung, Stephane M Ibraham Mazlan, Ruenn Chai Lai, Dominique P V de Kleijn, Sai Kiang Lim, A Mark Richards

Abstract

The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome with the active component(s) identified as exosomes underpinned our test of the efficacy of MSC exosomes in a porcine model of myocardial infarction (MI) when administered systemically by the convenient method of intravenous (IV) bolus injection. Results show that 7 days of IV exosomes results in clear reduction (30-40%) of infarct size measured at both 7 and 28 days post-MI, despite near identical release of hs Troponin T. Together with reduced infarct size, exosome treatment reduced transmurality and lessened wall thinning in the infarct zone. Exosome treated pigs showed relative preservation of LV function with significant amelioration of falls in fractional wall thickening 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. Taken together, these 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.

Keywords: cMRI; cardiac fibrosis; exosomes; left ventricular remodeling; mesenchymal stem cells; myocardial infarction; porcine (pig) model.

Copyright © 2020 Charles, Li, Yeung, Mazlan, Lai, de Kleijn, Lim and Richards.

Figures

Figure 1
Figure 1
Electron micrograph showing particles measuring between 50 and 100 nm labeled with gold beads indicating the presence of CD81+ particles.
Figure 2
Figure 2
(Top) Infarct size measured by cardiac magnetic resonance imaging (MRI) or post mortem left ventricle (LV) ring planimetry in ten pigs receiving 7 days intravenous administration of exosomes following myocardial infarction (MI) by means of left circumflex coronary artery ligation and ten pigs vehicle control treated MI pigs. (Lower) High sensitivity (hs) TroponinT plasma levels for 7 days post-MI in exosome (•) vs. control (°) treated pigs. Values shown are mean ± SEM. Significant differences at time-matched points between the exosomes and control pigs are indicated as follows: *p < 0.05 and †p < 0.01.
Figure 3
Figure 3
Examples of MRI post-gadolinium short axis images of left ventricle 28 days post-MI and corresponding gross pathology from post mortem left ventricular rings showing infarct vs. normal myocardium from a representative exosomes treated and control treated MI pig.
Figure 4
Figure 4
Representative examples of histology of the infarct region (A) H&E staining from control treated pig; (B) picrosirius red staining from control pig; (C) H&E from exosomes treated pig; (D) picrosirius red from exosomes pig. Scale bar for all images is 5000 um long.
Figure 5
Figure 5
Serial mid-slice end systolic (ES) wall thickness (left) and fractional wall thickening (right) measured by MRI across 6 sectors of the left ventricle spanning the infarct in ten pigs receiving 7 days intravenous administration of exosomes (•) following MI and ten pigs vehicle control (°) treated pigs. Values shown are mean ± SEM. Significant differences at time-matched points between the exosomes and control pigs are indicated as follows: *p < 0.05 and ‡p < 0.001.
Figure 6
Figure 6
Serial left ventricular end diastolic volume (EDV), end systolic volume (ESV), stoke volume, and ejection fraction measured by MRI in ten pigs receiving 7 days intravenous administration of exosomes (•) following MI and ten pigs vehicle control (°) treated pigs. Values shown are mean ± SEM. Significant differences at time-matched points between the exosomes and control pigs are indicated as follows: *p < 0.05.
Figure 7
Figure 7
Serial cardiac MRI T1 MOLLI values across 17 segments in ten pigs receiving 7 days intravenous administration of exosomes (•) following MI and ten pigs vehicle control (°) treated pigs. Values shown are mean ± SEM. Significant differences at time-matched points between the exosomes and control pigs are indicated as follows: *p < 0.05 and ‡p < 0.001.

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