ABSTRACT: BACKGROUND:Diabetic cardiomyopathy (DCM) is a cardiac complication of long-term uncontrolled diabetes and is characterized by myocardial fibrosis and abnormal cardiac function. Mesenchymal stem cells (MSCs) are multipotent cells with immunoregulatory and secretory functions in diabetes and heart diseases. However, very few studies have focused on the effect and the underlying mechanism of MSCs on myocardial fibrosis in DCM. Therefore, we aimed to explore the therapeutic potential of MSCs in myocardial fibrosis and its underlying mechanism in vivo and in vitro. METHODS:A DCM rat model was induced using a high-fat diet (HFD) combined with a low-dose streptozotocin (STZ) injection. After four infusions of MSCs, rat serum and heart tissues were collected, and the levels of blood glucose and lipid, cardiac structure, and function, and the degree of myocardial fibrosis including the expression levels of pro-fibrotic factor and collagen were analyzed using biochemical methods, echocardiography, histopathology, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA). We infused prostaglandin E2 (PGE2)-deficient MSCs to DCM rats in vivo and established a system mimicking diabetic myocardial fibrosis in vitro by inducing cardiac fibroblasts with high glucose (HG) and coculturing them with MSCs or PGE2-deficient MSCs to further explore the underlying mechanism of amelioration of myocardial fibrosis by MSCs. RESULTS:Metabolic abnormalities, myocardial fibrosis, and cardiac dysfunction in DCM rats were significantly ameliorated after treatment with MSCs. Moreover, the levels of TGF-?, collagen I, collagen III, and collagen accumulation were markedly decreased after MSC infusion compared to those in DCM hearts. However, PGE2-deficient MSCs had decreased ability to alleviate cardiac fibrosis and dysfunction. In addition, in vitro study revealed that the concentration of PGE2 in the MSC group was enhanced, while the proliferation and collagen secretion of cardiac fibroblasts were reduced after MSC treatment. However, MSCs had little effect on alleviating fibrosis when the fibroblasts were pretreated with cyclooxygenase-2 (COX-2) inhibitors, which also inhibited PGE2 secretion. This phenomenon could be reversed by adding PGE2. CONCLUSIONS:Our results indicated that MSC infusion could ameliorate cardiac fibrosis and dysfunction in DCM rats. The underlying mechanisms might involve the function of PGE2 secreted by MSCs.
