Hypoxic Preconditioned Tibetan Mesenchymal Stem Cell-derived Exosomes Ameliorate Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Rats

Abstract

BackgroundPulmonary hypertension associated with hypoxia frequently manifests in a range of long-standing lung disorders. A strategy to augment the therapeutic efficacy of mesenchymal stem cells (MSCs) involves subjecting them to hypoxic preconditioning, which bolsters the emission of exosomes exhibiting enhanced bioactivities through paracrine mechanisms. The objective of this research is to explore the healing impact of preconditioning with hypoxia on MSC-extracted exosomes in relation to vascular structural changes within the lungs of rodents afflicted by hypoxia-induced pulmonary arterial hypertension. Methods and ResultsThis research entailed the successful isolation, cultivation of mesenchymal stem cells from Tibetan umbilical cords, alongside the extraction of their exosomes. Our results highlight that exosomes derived from hypoxia-conditioned Tibetan cord mesenchymal stem cells (H-Tibetan-exo) demonstrated superior efficacy in suppressing pulmonary vascular structural changes compared to those from normoxic conditions (N-Tibetan-exo) in a rat model of hypoxia-induced pulmonary hypertension (HPH).In an effort to replicate pulmonary hypertension conditions within a laboratory setting, we subjected rat pulmonary arterial smooth muscle cells (rPASMCs) to a low oxygen environment. Our findings revealed that exosomes derived from high-altitude Tibetans (H-Tibetan-exo) showed a superior capacity in suppressing the growth of rPASMCs compared to those obtained from normoxic Tibetans (N-Tibetan-exo). Additionally, the Transwell assay revealed a more significant inhibition of rPASMCs migration by H-Tibetan-exo. The investigation of PI3K-AKT-mTOR pathway protein expression through western blot analysis revealed that under hypoxic conditions, there was an elevation in the phosphorylation status of these proteins in both cellular and tissue settings. Furthermore, the H-Tibetan-exo exhibited more effective inhibition of rPASMCs proliferation and a more significant downregulation of PI3K-AKT-mTOR pathway protein phosphorylation levels compared to the N-Tibetan-exo. ConclusionsH-Tibetan-exo significantly ameliorates pulmonary vascular remodeling in hypoxic pulmonary hypertension more effectively than N-Tibetan-exo. The enhancement observed could be linked to reduced activity of the PI3K-AKT-mTOR pathway. This discovery sheds fresh light on managing hypoxic pulmonary hypertension, highlighting the potential therapeutic benefits of H-Tibetan-exo in mitigating its development.