Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling
Open Access
- 20 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Respiratory Research
- Vol. 21 (1), 1-12
- https://doi.org/10.1186/s12931-020-1331-4
Abstract
Background Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, right ventricular hypertrophy and failure. So far no effective treatment exists for this disease; hence, novel approaches are urgently needed. The aim of the present research was to observe the treatment effect of mesenchymal stromal cell derived exosomes and reveal the mechanism. Methods Monocrotaline (MCT)-induced PH in rats and hypoxia-induced cell damage model were established, respectively. Exosomes derived from the supernatant of human umbilical cord mesenchymal stem cells (MSC-exo) were injected into MCT-PH model rat or added into the cells cultured medium. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods were used in vivo and vitro. Results The results showed that MSC-exo could significantly attenuate right ventricular (RV) hypertrophy and pulmonary vascular remodelling in MCT-PH rats. In the cell culture experiments, we found that MSC-exo could significantly inhibit hypoxia-induced pulmonary arterial endothelial cell (PAEC) apoptosis and pulmonary arterial smooth muscle cells (PASMC) proliferation. Furthermore, the pulmonary arterioles endothelial-to-mesenchymal transition (EndMT) was obviously suppressed. Moreover, the present study suggest that MSC-exo can significantly upregulate the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Furthermore, with Wnt5a gene silencing, the therapeutic effect of MSC-exo against hypoxia injury was restrained. Conclusions Synthetically, our data provide a strong evidence for the therapeutic of MSC-exo on PH, more importantly, we confirmed that the mechanism was associated with up-regulation of the expression of Wnt5a. These results offer a theoretical basis for clinical prevention and treatment of PH.This publication has 38 references indexed in Scilit:
- Exosomes Mediate the Cytoprotective Action of Mesenchymal Stromal Cells on Hypoxia-Induced Pulmonary HypertensionCirculation, 2012
- Dvl2-Dependent Activation of Daam1 and RhoA Regulates Wnt5a-Induced Breast Cancer Cell MigrationPLOS ONE, 2012
- Implantation of Mesenchymal Stem Cells Improves Right Ventricular Impairments Caused by Experimental Pulmonary HypertensionThe American Journal of the Medical Sciences, 2012
- Glycogen Synthase Kinase 3beta Contributes to Proliferation of Arterial Smooth Muscle Cells in Pulmonary HypertensionPLOS ONE, 2011
- WNT5A Is a Regulator of Fibroblast Proliferation and Resistance to ApoptosisAmerican Journal of Respiratory Cell and Molecular Biology, 2009
- Airway smooth muscle hyperplasia and hypertrophy correlate with glycogen synthase kinase-3β phosphorylation in a mouse model of asthmaAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2009
- Regression of chronic hypoxic pulmonary hypertension by simvastatinAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
- The transforming growth factor- /Smad2,3 signalling axis is impaired in experimental pulmonary hypertensionEuropean Respiratory Journal, 2007
- Expression of Wnt-5a Is Correlated with Aggressiveness of Gastric Cancer by Stimulating Cell Migration and InvasionCancer Research, 2006
- A Role for the β-Catenin/T-Cell Factor Signaling Cascade in Vascular RemodelingCirculation Research, 2002