Abstract
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-exoTIMP2) on the MI rat model. The huc-exoTIMP2 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-exoTIMP2 administration increased the in situ expression of the antiapoptotic Bcl-2 and decreased that of the proapoptotic Bax and pro-caspase-9 in the infracted myocardium. Meanwhile, huc-exoTIMP2 upregulated superoxide dismutase (SOD) as well as glutathione (GSH) and decreased the malondialdehyde (MDA) level in MI models. In vitro huc-exoTIMP2 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 TGFβ-induced MMP2, MMP9, and α-SMA secretion by cardiac fibroblasts (CFs). Besides that, huc-exoTIMP2 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-exoTIMP2, indicating a mechanistic basis of its action. Importantly, Sfrp2 knockdown in huc-exoTIMP2 abrogated the protective effects. Taken together, huc-exoTIMP2 improved cardiac function by alleviating MI-induced oxidative stress and ECM remodeling, partly via the Akt/Sfrp2 pathway.
Highlights
Myocardial infarction (MI) results in the loss of cardiomyocytes and adverse remodeling of the extracellular matrix (ECM)
Characterization of human umbilical cord mesenchymal stem cells (hucMSCs) and hucMSC-Derived Exosomes. hucMSCs cultured in vitro showed the characteristic spindle-shaped morphology and were able to differentiate into adipocytes and osteocytes in response to appropriate inducement (Figure 1(a))
Mass spectrometry analysis showed high endogenous levels of the TIMP2 protein in the hucMSCs-exo (Figure 1(c)), and overexpression of the exogenous TIMP2 in hucMSCs was validated by qPCR and Western blotting (Figure 1(d))
Summary
Myocardial infarction (MI) results in the loss of cardiomyocytes and adverse remodeling of the extracellular matrix (ECM). The major mechanism underlying cardiomyocyte loss in the infarcted myocardium is oxidative stress [1], due to excessive reactive oxygen species (ROS) production, which impairs cellular functions and viability [2]. Improving cardiomyocyte survival and inhibiting apoptosis may be crucial for improving the prognosis of ischemic disease. The cardiac fibroblasts could be activated by myocardial injury triggering adverse ECM remodeling and excessive fibrosis. The ECM primarily composes of the type I and the type III collagen, which are crucial to maintain the normal cardiac structure, myocardial force, and myocardial systolic and diastolic coordination. Despite a plethora of treatments for MI, restoration of the scarred myocardial tissue is limited due to the nonrenewable nature of the myocardial cells [3]
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