Vascular Medicine Exosomes Mediate the Cytoprotective Action of Mesenchymal Stromal Cells on Hypoxia-Induced Pulmonary Hypertension

Background—Hypoxia induces an inflammatory response in the lung manifested by alternative activation of macrophages with elevation of proinflammatory mediators that are critical for the later development of hypoxic pulmonary hypertension. Mesenchymal stromal cell transplantation inhibits lung inflammation, vascular remodeling, and right heart failure and reverses hypoxic pulmonary hypertension in experimental models of disease. In this study, we aimed to investigate the paracrine mechanisms by which mesenchymal stromal cells are protective in hypoxic pulmonary hypertension. Methods and Results—We fractionated mouse mesenchymal stromal cell– conditioned media to identify the biologically active component affecting in vivo hypoxic signaling and determined that exosomes, secreted membrane microvesicles, suppressed the hypoxic pulmonary influx of macrophages and the induction of proinflammatory and proproliferative mediators, including monocyte chemoattractant protein-1 and hypoxia-inducible mitogenic factor, in the murine model of hypoxic pulmonary hypertension. Intravenous delivery of mesenchymal stromal cell– derived exosomes (MEX) inhibited vascular remodeling and hypoxic pulmonary hypertension, whereas MEX-depleted media or fibroblast-derived exosomes had no effect. MEX suppressed the hypoxic activation of signal transducer and activator of transcription 3 (STAT3) and the upregulation of the miR-17 superfamily of microRNA clusters, whereas it increased lung levels of miR-204, a key microRNA, the expression of which is decreased in human pulmonary hypertension. MEX produced by human umbilical cord mesenchymal stromal cells inhibited STAT3 signaling in isolated human pulmonary artery endothelial cells, demonstrating a direct effect of MEX on hypoxic vascular cells. Conclusion—This study indicates that MEX exert a pleiotropic protective effect on the lung and inhibit pulmonary hypertension through suppression of hyperproliferative pathways, including STAT3-mediated signaling induced by hypoxia. T he response of the lungs to low levels of environmental oxygen is multifactorial. Diverse signaling pathways, activated or impaired by alveolar hypoxia, converge on endothelial and vascular smooth muscle cells to perturb pulmonary vascular homeostasis. Chronic hypoxia results in pulmonary vascular remodeling, a key pathological feature of pulmonary hypertension (PH). Inflammation plays a prominent detrimental role in most types of human PH and in animal models of the disease such as the monocrotaline-induced PH and hypoxia-induced PH (HPH) in rodents. The early component of hypoxia-induced lung inflammation, peaking during the first 2 to 3 days of hypoxic exposure, 1 is characterized by alternative activation of alveolar macro-phages and appears to be causal to the subsequent vascular remodeling and the development of HPH. 2 Despite the significant progress in our understanding of the pathophysiology of PH and the treatment of its …