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.
Highlights
The potential of cell-based therapies to stimulate cardiac regeneration following myocardial infarction (MI) has been investigated for two decades with many pre-clinical studies showing promise but mixed results from clinical studies to date and some controversy resulting from fraudulent publications [1]
Differences in infarct size between the exosome treated and untreated pigs were obvious on both MRI, day 7 and day 28 (Figure 3), and gross histological examination of the PM left ventricular (LV) rings as shown in Figure 3 by exemplar MRI images and PM photographs of heart rings, left circumflex (LCX) ligation in control pigs resulted in significant transmural infarcts involving ∼25–35% of the circumference of the LV wall extending from the basal slice through to 3-4 of 5 LV rings with obvious wall thinning and well developed scar tissue
The observations that mesenchymal stem cells (MSCs) exert cardiac protection and repair via their secretome and that the active component(s) of MSC conditioned medium is/are carried by exosomes underpinned our test of the efficacy of MSC exosomes in a large animal model of MI when administered systemically by the convenient method of IV bolus injection
Summary
The potential of cell-based therapies to stimulate cardiac regeneration following myocardial infarction (MI) has been investigated for two decades with many pre-clinical studies showing promise but mixed results from clinical studies to date and some controversy resulting from fraudulent publications [1] Stem cell types such as mesenchymal stem cells (MSC) derived from bone marrow have been shown to have potent effects through multiple mechanisms [2] despite. Our group was the first to show that exosomes carried the active component(s) of MSC conditioned medium and that infused MSC exosomes reduce I/R injury in mice [10, 11] Together, these and other studies provide key evidence for the paracrine hypothesis whereby MSC therapeutic efficacy is mediated primarily via the MSC secretome. As reviewed by our group [12], MSC exosomes carry many of the therapeutic agent(s) in MSC secretion
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