Proteomic basis of modulation of post ischemic fibrosis by MSC exosomes

Following an ischemic event, there is activation of fibroblasts leading to scar formation. It is critical to limit the pro-fibrotic remodeling and activate the reparative, remodeling phase to limit cardiac diastolic dysfunction. Mesenchymal stem cell (MSC) exosomes offer significant protection against ischemia-related systolic dysfunction. Here we studied if MSC exosomes would offer protection against pro-fibrotic events in mouse hearts subjected to acute ischemia (1 hr. left coronary artery occlusion [LCA]) or chronic ischemia (7 days LCA occlusion). Following acute ischemia, there was activation of inflammatory signals, more in the peri-infarct than in the infarct area, in the saline (vehicle)-treated mice. At the same time, there was expression of cardiac remodeling signals (vimentin, collagens-1 and -3, and fibronectin), more in the infarct area. Treatment with MSC exosomes before LCA ligation suppressed inflammatory signals during acute as well as chronic ischemia. Further, exosome treatment promoted pro-reparative cardiac ECM remodeling, in both infarct and peri-infarct areas by suppressing fibronectin secretion and by modulating collagen secretion to reduce fibrotic scar formation through altered cellular signaling pathways. Proteomics study revealed intense expression of IL-1b and activation of pro-fibrotic signals in the saline-treated hearts and their suppression in MSC exosome-treated hearts. To our knowledge, this is the first report on the infarct and peri-infarct area proteomics of ischemic mice hearts to explain MSC exosome-mediated suppression of scar formation in the ischemic mouse hearts.