Cells are logistically challenging and more expensive to work with in comparison to components of cell signaling such as proteins or extracellular vesicles. In cell therapies wherein the bulk of the benefit is due to signaling by the transplanted cells - which is the case for near all first generation stem cell therapies, in which the newly introduced cells have a very low survival rate - it makes a lot of sense to isolate the relevant signals and deliver those instead of cells. Since a majority of signaling is transported via classes of extracellular vesicle, such as exosomes, many development programs now focus on the delivery of harvested exosomes rather than cultured cells, well in advance of a full understanding of the beneficial signals involved.
Cell transplant has been an attractive potential therapy for cardiovascular disease; however, poor cell engraftment limits efficacy of the approach. We here compared transplanting a mixture of human induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, and smooth muscle cells to transplant of exosomes produced by these cells in a pig model of myocardial infarction. They saw similar improvements in cardiac function in cell, cell fragment, and exosome transplant groups without evidence of increased arrhythmogenicity.
We compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after myocardial infarction (MI). Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium.
In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.