Microvessel co-transplantation improves poor remuscularization by hiPSC-cardiomyocytes in a complex disease model of myocardial infarction and type 2 diabetes.

Abstract

People with type 2 diabetes (T2D) are at a higher risk for myocardial infarction (MI) than age-matched healthy individuals. Here, we studied cell-based cardiac regeneration post MI in T2D rats modeling the co-morbid conditions in patients with MI. We recapitulated the T2D hallmarks and clinical aspects of diabetic cardiomyopathy using high-fat diet and streptozotocin in athymic rats, which were then subjected to MI and intramyocardial implantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with or without rat adipose-derived microvessels (MVs). hiPSC-CM alone engrafted poorly. Co-delivery of hiPSC-CMs with MVs yielded a smaller infarct area and a thicker left ventricle wall. Additionally, MVs robustly integrated into the infarcted hearts, improved the survival of hiPSC-CMs, and improved cardiac function. MV-conditioned media also promoted hiPSC-CM maturation in vitro, increasing cardiomyocyte (CM) size in an interleukin (IL)-6-dependent manner. Given the availability of MVs from human adipose tissue, MVs present great translational potential for the treatment of heart failure in people with T2D.