Proteomic basis of modulation of postischemic fibrosis by MSC exosomes.

Abstract

After an ischemic event, there is activation of fibroblasts leading to scar formation. It is critical to limit the profibrotic 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 profibrotic events in mouse hearts subjected to acute ischemia [1 h left coronary artery (LCA) occlusion] or chronic ischemia (7 days LCA occlusion). After 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 and chronic ischemia. Furthermore, exosome treatment promoted pro-reparative cardiac extracellular matrix (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-1β and activation of profibrotic 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.