PAH is a progressive disorder characterized by the progressive increase in pulmonary arterial pressure and resistance, eventually leading to right heart failure and mortality in patients with refractory disease. Although in the past ten years, the treatment of PAH has achieved apparent progress, the prognosis remains poor. Intravenous administration of drugs (e.g. prostacyclin, endothelin receptor antagonists) or nitric oxide inhalation may temporarily reduce PAH, but these effects are not lasting. In recent years, regeneration and gene therapy has become the research focus worldwide, however, stem cell research is still in its initial stages and so far there is no uniform method to treat PAH. Therefore, for further experimental studies, investigating reasonable and safe methods of treatment for PAH has become urgent.
BMSCs, multipotent progenitor cells derived from fetal bone marrow, could differentiate into distinctive end-stage cell types, including bone, cartilage, muscle, endothelial cells, vascular smooth muscle cells and other connective tissues. Studies have also demonstrated that BMSCs have the pluripotent ability to become endothelial progenitor cells and other cell lineages (15
). BMSCs are able to secrete a variety of growth factors to promote angiogenesis, such as VEGF.
Transplantation of endothelial progenitor cells (EPCs) into the MCT-injured lung could repair the damage, but the treatment effect is not ideal. The studies on BMSC transplantation for pulmonary hypertension are limited. In our previous research (17
), intravenous implantation of BMSCs improved the progression of RV impairment caused by MCT-induced PAH. The aim of this study was to further explore the effect of BMSCs on lung and heart impairment. First, we demonstrated that 2 weeks after sublingual vein administration of BMSCs to PAH rats, the pulmonary arterial pressure was significantly lower in the BMSC group compared with the nontreated PAH group. RVSP, MRVP and MPAP were significantly lower in the BMSC group compared with the PAH group, the ratio of RV/BW was significantly lower in the BMSC group compared with the PAH group. Notably, in the case of the present study, we found that the structural changes in the pulmonary vascular wall, such as VA and TAA, were significantly improved. Although the underlying mechanisms are complicated and not yet determined, several factors are expected to contribute, including the role of stem cell differentiation and para-secretion effects (3
). Our experiments also demonstrated that the red fluorescence-positive cells were observed coincident with the green fluorescence spots of VEGF and vWF antibody but not SP-C antibody in numerous regions. These results suggest that the intravenous implantation of BMSCs results in the ability of these cells to differentiate into vascular endothelial cells in vivo
but not lung cells. Therefore, transplantation of BMSCs by homing to the lung and transforming into vascular endothelial cells may create a wide range of collateral circulation, increase the total area of the pulmonary vascular bed, improve pulmonary blood supply and effectively reduce the pulmonary hypertension.
In conclusion, our results showed that intravenous implantation of BMSCs may improve not only the cardiac function and hemodynamics, but also the pulmonary vascular wall damage in PAH caused by MCT. Therefore, this study provides conslusive information for the use of this new method in the treatment of pulmonary arterial hypertension.