For decades, stem cell
therapies for
pulmonary hypertension (PH) have progressed from laboratory hypothesis to clinical practice. Promising preclinical investigations have laid both a theoretical and practical foundation for clinical application of mesenchymal stem cells (MSCs) for PH
therapy. However, the underlying mechanisms are still poorly understood. We sought to study the effects and mechanisms of MSCs on the treatment of PH. For in vivo experiments, the transplanted GFP+ MSCs were traced at different time points in the lung tissue of a chronic
hypoxia-induced PH (
CHPH) rat model. The effects of MSCs on PH pathogenesis were evaluated in both
CHPH and sugen
hypoxia-induced PH models. For in vitro experiments, primary pulmonary microvascular endothelial cells were cultured and treated with the MSC
conditioned medium. The specific markers of endothelial-to-mesenchymal transition (EndMT) and cell migration properties were measured. MSCs decreased pulmonary arterial pressure and ameliorated the
collagen deposition, and reduced the thickening and muscularization in both
CHPH and sugen
hypoxia-induced PH rat models. Then, MSCs significantly attenuated the
hypoxia-induced EndMT in both the lungs of PH models and primary cultured rat pulmonary microvascular endothelial cells, as reflected by increased mesenchymal cell markers (
fibronectin 1 and
vimentin) and decreased endothelial cell markers (
vascular endothelial cadherin and
platelet endothelial cell adhesion molecule-1). Moreover, MSCs also markedly inhibited the
protein expression and degradation of
hypoxia-inducible factor-2α, which is known to trigger EndMT progression. Our data suggest that MSCs successfully prevent PH by ameliorating pulmonary
vascular remodeling,
inflammation, and EndMT.
Transplantation of MSCs could potentially be a powerful therapeutic approach against PH.