Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension.

Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.