Targeting regenerative exosomes to myocardial infarction using cardiac homing peptide

Vandergriff, Adam; Huang, Ke; Shen, Deliang; Hu, Shiqi; Hensley, Michael Taylor; Caranasos, Thomas G.; Qian, Li; Cheng, Ke

After a long period of dormancy since the discovery of exosomes in the 1980's [36] [37] [38] [39] [40] , researchers have begun to understand the value of exosomes and their importance in cell-to-cell signaling. Exosomes secreted by cardiospherederived stem cells have been shown to promote cardiac regeneration [18, 20, 41] . It has been indicated that the beneficial effects of exosomes are due to its ability to shuttle miRNA between cells [11] [12] [13] [14] [15] [16] . CDC-XOs contain numerous miRNAs, in particular miR21 and miR146a [18] , both of which have been shown to have beneficial effects on the injured myocardium [42] [43] [44] [45] [46] . miR21 reduces myocardial apoptosis by modulating expression of programmed cell death 4 (PDCD4), FasL, and AKT pathways [47] [48] [49] . miR146a represses interleukin-1 receptorassociated kinase1 (IRAK1) and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), reducing activation of nuclear factor κΒ (NF-κΒ) [18, 44] . The effects of the miRNAs do not appear to be the result of any single miRNA, but rather the effects are dependent upon multiple miRNAs working in tandem [18, 49] . When combined, miR21 and miR146a result in significant reduction of p38 mitogenassociated kinase phosphorylation (p-p38 MAPK) [49] . As miRNAs do not require an exact match to the target mRNA, miRNAs can repress many different proteins [50] [51] [52] [53] [54] [55] [56] . When co-expressed or inhibited, this leads to multiple interactions and alterations as overlapping portions of pathways are modulated [50, [57] [58] [59] . Of the many possible outcomes of the miRNA modulation, we demonstrate that CHP-XOs promote cardiac repair through reduced scar size ( Figure 3D-E) , increased cardiac proliferation ( Figure 4A-B) , and increased angiogenesis (Figure 4C-D) .