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

Abstract

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 O2 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.

Bovine Oviduct Epithelial Cell-Derived Culture Media and Exosomes Improve Mitochondrial Health by Restoring Metabolic Flux during Pre-Implantation Development

“…Our observations showed that the effect on the glycolytic metabolic pathway was more pronounced in the Exo exclusive treatment group than in the BOECs-CM supplementation group. These effects of Exo treatment echo a similar effect, the improvement of the TCA cycle which was reported in Exo derived from mesenchymal stromal cells, improved the mitochondrial function deficiencies in an in vitro culture model of human pulmonary artery smooth muscle cells [ 35 ]. The upregulation of TCA cycle metabolizing genes is a signature of improved mitochondrial health [ 9 , 10 ].…”

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling

“…The pathogenesis of PH is not clear yet, therefore, so far there is still no effective prevention measures for it. Previous studies have suggested the exosomes isolated from mesenchymal stem cells (MSCs) has the potential to inhibition of vascular remodeling in PH, which is considered as a novel potential therapeutic approach for the treatment of PH [10,11,15]. However, the mechanism is not fully clear.…”

“…MSC-derived exosomes (MSC-exo) is one of the main therapeutic vectors in MSCs, which act as vehicles transmission of protein species in the cells directly affect the receptor cells gene expression and cell phenotype. Several studies have shown that that intravenous delivery of MSC-exo can inhibit PH vascular remodeling [9][10][11], however, the molecular mechanism is still not clear.…”

The emerging antioxidant paradigm of mesenchymal stem cell therapy

“…Increased levels of GSSG to GSH are suggestive of an oxidative redox state. Conversely, higher GSH‐to‐GSSG ratio is observed after MSC treatment in models of type 2 diabetes, in the hippocampus after chronic ethanol intake and hypoxia‐induced hypertension 85‐87 . Likewise, MSCs improve GSH‐to‐GSSG ratio in sepsis which is not achieved by fibroblast 51 .…”