Exosomes Derived from TIMP2-Modified Human Umbilical Cord Mesenchymal Stem Cells Enhance the Repair Effect in Rat Model with Myocardial Infarction Possibly by the Akt/Sfrp2 Pathway

Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) are a promising new therapeutic option for myocardial infarction (MI). The tissue matrix metalloproteinase inhibitor 2, also known as TIMP2, is a member of the tissue inhibitor family of metalloproteinases. Since TIMP2-mediated inhibition of matrix metalloproteinases (MMPs) is a key determinant of post-MI remodeling, we analyzed the therapeutic effects of exosomes derived from TIMP2-overexpressing hucMSCs (huc-exo(TIMP2)) on the MI rat model. The huc-exo(TIMP2) significantly improved in vivo cardiac function as measured by echocardiography and promoted angiogenesis in MI injury. It also restricted extracellular matrix (ECM) remodeling, as indicated by the reduced collagen deposition. In addition, huc-exo(TIMP2) administration increased the in situ expression of the antiapoptotic Bcl-2 and decreased that of the proapoptotic Box and pro-caspase-9 in the infracted myocardium. Meanwhile, huc-exo(TIMP2) upregulated superoxide dismutase (SOD) as well as glutathione (GSH) and decreased the malondialdehyde (MDA) level in MI models. In vitro huc-exo(TIMP2) pretreatment could inhibit H2O2-mediated H9C2-cardiomyocyte apoptosis and promote human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation, as well as decrease TGF beta-induced MMP2, MMP9, and alpha-SMA secretion by cardiac fibroblasts (CFs). Besides that, huc-exo(TIMP2) pretreatment also increased the expression of Akt phosphorylation in the infarcted myocardium, which may relate to a high level of secreted frizzled-related protein 2 (Sfrp2) in huc-exo(TIMP2), indicating a mechanistic basis of its action. Importantly, Sfrp2 knockdown in huc-exo(TIMP2) abrogated the protective effects. Taken together, huc-exo(TIMP2) improved cardiac function by alleviating MI-induced oxidative stress and ECM remodeling, partly via the Akt/Sfrp2 pathway.