Exosomes Derived from Human Mesenchymal Stem Cells Protect Against Cardiomyocyte Injury in Type II Diabetes

Exosomes are emerging as an effective therapeutic tool for various diseases. These sub-micron-sized vesicles are secreted by different cell-types and participate in intercellular communication by fusing with a recipient cell’s membrane and delivering a protein or RNA payload. Exosomes derived from human mesenchymal stem cells (MSCs) can deliver beneficial effects that mimic MSC-based therapies while avoiding many of the risks associated with traditional MSC transplantation. Our goal is to understand the role of exosomes on the susceptibility of the diabetic heart to develop cardiomyopathy.

Methods: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin (AT) using an osmotic pump at a rate of 1000ng·kg−1·min−1 for 30-days. Exosomes purified from human MSCs (1.5 × 10⁹) were administered intravenously with AT once a week. Myocyte cultures (in-vitro) containing different glucose levels (25 and 33 mM) were incubated with labeled exosomes (2.8 × 10⁸) for 24-hours and AT 1 μM. Mitochondrial ROS production was detected using a 2′,7′-Dichlorofluorescin diacetate reagent.

Results: Concomitant infusion of exosomes and AT reduced free blood glucose compared to non-treated db/db mice (1,045 ± 148 vs. 657 ± 45mg/dl). Troponin-T and heart weight were elevated in diabetic mice treated with AT but decreased to normal values following exosome treatment.

Using fluorescent membrane tracer (PKH), in-vitro experiments demonstrated that exosomes penetrate the cardiomyocyte cytoplasm without entering the nucleus independently of glucose levels or AT treatment. Myocyte cultures containing different glucose levels showed no difference in ROS production or the number of exosomes entering the cells.

Conclusions: Our results suggest that exosomes may have direct and indirect protective effects on the diabetic heart. These results support the concept that exosomes may be used to protect cardiomyocytes against diabetes.