ABSTRACT
Bone marrow mesenchymal stem cell (BM-MSC) transplantation has been suggested to be a promising method for the treatment of pulmonary arterial hypertension (PAH), a fatal disease currently without effective preventive/therapeutic strategies. However, the detailed mechanisms underlying BM-MSC therapy are largely unknown. We designed the present study to test the hypothesis that circulating platelets facilitate BM-MSC homing to the lung vasculature in a rat model of PAH induced by monocrotalin (MCT). A single subcutaneous administration of MCT induced a marked rise in right ventricular systolic pressure (RVSP) and the weight ratio of right to left ventricle plus septum (RV/LV+S) 3 weeks after injection. The injection of MSCs via tail vein 3 days after MCT significantly reduced the increase of RVSP and RV/LV+S. The fluorescence-labeled MSCs injected into the PAH rat circulation were found mostly distributed in the lungs, particularly on the pulmonary vascular wall, whereas cell homing was abolished by an anti-P-selectin antibody and the GPIIb/IIIa inhibitor tirofiban. Furthermore, using an in vitro flow chamber, we demonstrated that MSC adhesion to the major extracellular matrix collagen was facilitated by platelets and their P-selectin and GPIIb/IIIa. Therefore, the current study suggested that platelet-mediated MSC homing prevented the aggravation of MCT-induced rat PAH, via P-selectin and GPIIb/IIIa-mediated mechanisms.
Subject(s)
Blood Platelets/metabolism , Hypertension, Pulmonary/therapy , Lung/cytology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/cytology , Animals , Antibodies/pharmacology , Blood Pressure , Bone Marrow Cells/cytology , Familial Primary Pulmonary Hypertension , Heart Ventricles/physiopathology , Hemodynamics , Hypertension, Pulmonary/chemically induced , Lung/drug effects , Male , Monocrotaline/toxicity , P-Selectin/immunology , P-Selectin/metabolism , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Platelet Glycoprotein GPIIb-IIIa Complex/metabolism , Rats , Rats, Sprague-Dawley , Tirofiban , Tyrosine/analogs & derivatives , Tyrosine/pharmacologyABSTRACT
Distant metastasis is the main cause of cancer death. Tetraspanins (transmembrane 4 superfamily, TM4SF) is capable of forming transmembrane complexes with integrin family participating in cell adhesion, migration and tumor metastasis. This review elucidates the structure of tetraspanins and its function in regulating metastasis as form of multimolecular transmembrane complexes with integrin.
