Mesenchymal stromal cell derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling
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.
Respiratory Research