Abstract
BackgroundDiabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM.MethodsPrimary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle).ResultsSMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group.ConclusionsTreatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.
Highlights
Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting
Animal care and biosafety Wistar rats were obtained from Charles River Laboratories, and enhanced green fluorescent protein (EGFP)transgenic Sprague–Dawley rats were purchased from Rat Resource and Research Center (RRRC)
After mesenchymal stem cell (MSC)-toSMC differentiation, the cells were highly positive for α-smooth muscle actin (αSMA) (70.8 ± 9.8%) and SM22α (76.9 ± 9.1%, Fig. 1b, c, k)
Summary
Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). The global prevalence of diabetes mellitus (DM) is rapidly increasing, and patients suffering from this disease have a significantly increased risk of cardiovascular disease and death [1]. DM is a significant risk factor for mortality and repeat coronary revascularization after coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) [3,4,5]. The adverse impact of DM is even more pronounced in the setting of cardiomyopathy, as patients with low left ventricular ejection fraction (LVEF) do not benefit from CABG when they have coexistent DM [6]. The treatment of CAD in the diabetic heart is challenging
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