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

Abstract

Background Hypoxia induces an inflammatory response in the lung manifested by alternative activation of macrophages with elevation of pro-inflammatory mediators that are critical for the later development of hypoxic pulmonary hypertension (HPH). Mesenchymal stromal cell (MSC) transplantation inhibits lung inflammation, vascular remodeling and right heart failure, and reverses HPH in experimental models of disease. In this study, we aimed to investigate the paracrine mechanisms by which MSCs are protective in HPH. Methods and Results We fractionated mouse MSC-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 pro-inflammatory and pro-proliferative mediators, including monocyte chemoattractant protein-1 and hypoxia-inducible mitogenic factor, in the murine model of HPH. Intravenous delivery of MSC-derived exosomes (MEX) inhibited vascular remodeling and HPH, 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 whose expression is decreased in human PH. MEX produced by human umbilical cord MSCs inhibited STAT3 signaling in isolated human pulmonary artery endothelial cells demonstrating a direct effect of MEX on hypoxic vascular cells. Conclusions This study indicates that MEX exert a pleiotropic protective effect on the lung and inhibit PH through suppression of hyperproliferative pathways, including STAT-3 mediated signaling induced by hypoxia.

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…Bruno et al 68,71 Microvesicles derived from human MSCs had protective eff ects in both in-vitro and in-vivo acute kidney injury models Lee et al 72 Intravenous administration of MSC-derived exosomes decreased the infl ux of infl ammatory mediators and inhibited vascular remodelling and pulmonary hypertension in a murine model of hypoxia-induced pulmonary hypertension…”

Stromal cells–are they really useful for GVHD?

“…31,54,67 STROMAL CELL-DERIVED EXOSOMES AND MICROVESICLES Exosomes and microvesicles are small but complex entities that contain both immunomodulatory proteins and microRNA, and have homing abilities. 68 69 MSC-derived microvesicles have been shown to protect from acute kidney injury, 70 myocardial ischemia 71 and pulmonary hypertension 72 in animal models ( Table 3). The regenerative capacities of microvesicles appear to be at least partly dependent on the mRNA cargo, as treatment with RNAase to inactivate the mRNA content abrogated the protective effects.…”

Vascular Remodeling Process in Pulmonary Arterial Hypertension, with Focus on miR‐204 and miR‐126 (2013 Grover Conference Series)

“…14 Interestingly, miR-204 has already been shown to be decreased in plexiform vasculopathy of severe PAH in humans, 49 predicted to be a disease-modifying miRNA in PAH, 50 and established as a critical actor in a hypoxia-induced pulmonary hypertension mouse model. 51 Abated miR-204 levels were also associated with decreased apoptosis, enhanced cell proliferation, 52 and membrane depolarization, 53,54 the most common alterations observed in PAH-PASMC. In addition, it has been shown that this pro-proliferative phenotype is associated with activation of the Src-STAT3 and NFAT pathway (Fig.…”