Stem Cell Exosomes as Paracrine Mediators of CardioProtection and Repair

There have now been several basic science and clinical studies that demonstrate benefit of mesenchymal stem cell (MSC) injection post-myocardial infarction (MI). Specifically, there has been reported reduction of infarct/scar size, increased muscle, improved function, and preserved ejection fraction. However, the mechanism of these reparative effects are incompletely elucidated. It is generally agreed that muscle regeneration is not the basis for all of these effects, and that paracrine mechanisms are operative. Several groups, including ours, have implicated exosomes and their cargo, including microRNA (miR). We performed miRNA and mRNA deep sequencing from MSC and their exosomes and determined a set of cardioprotective miRs that are transferred to myocardium via exosomes. The miRs act in cardioprotection by simultaneously suppressing independent pathways to achieve a synergistic effect upon cell survival post-MI. The enhanced myocardial salvage is one of the key mechanisms involved in cardiac repair post-MI and results in a 68% reduction in infarct size normalized to risk region. Removal of miR-21, the most prevalent miR, reduces this effect to 28%, a reduced but significant level of cardioprotection. Whether additional effects of repair, including cell proliferation, angiogenesis, fibrosis, inflammation, and stem cell homing are similarly regulated and the exact miRs involved are topics of ongoing research. MSC exosomes whether native, or manipulated to maximize efficacy may be a useful off the shelf therapeutic for repair of injured tissues post-ischemia and trauma. The challenges are to define and engineer the cargo activities and to employ efficient tissue targeting to maximize efficacy and reduce adverse effects.