1. Let-7a-transfected mesenchymal stem cells ameliorate monocrotaline-induced pulmonary hypertension by suppressing pulmonary artery smooth muscle cell growth through STAT3-BMPR2 signaling.
- Author
-
Cheng G, Wang X, Li Y, and He L
- Subjects
- Adenoviridae genetics, Adenoviridae metabolism, Animals, Bone Morphogenetic Protein Receptors, Type II metabolism, Coculture Techniques, Gene Expression Regulation, Genetic Vectors chemistry, Genetic Vectors metabolism, Humans, Hypertension, Pulmonary chemically induced, Hypertension, Pulmonary pathology, Hypertension, Pulmonary physiopathology, Hypertrophy, Right Ventricular chemically induced, Hypertrophy, Right Ventricular pathology, Hypertrophy, Right Ventricular physiopathology, Lung blood supply, Lung pathology, Lung physiopathology, Male, Mesenchymal Stem Cells cytology, MicroRNAs metabolism, Monocrotaline, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle pathology, Pulmonary Artery metabolism, Pulmonary Artery pathology, Rats, Rats, Inbred Lew, STAT3 Transcription Factor metabolism, Signal Transduction, Transfection, Bone Morphogenetic Protein Receptors, Type II genetics, Hypertension, Pulmonary therapy, Hypertrophy, Right Ventricular therapy, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells metabolism, MicroRNAs genetics, STAT3 Transcription Factor genetics
- Abstract
Background: Cell-based gene therapy has become a subject of interest for the treatment of pulmonary arterial hypertension (PAH), a devastating disease characterized by pulmonary artery smooth muscle cell (PASMC) hyperplasia. Mesenchymal stem cells (MSCs) have been recently acknowledged as a potential cell vector for gene therapy. Here, we investigated the effect of MSC-based let-7a for PAH., Methods: After isolation and identification of MSCs from rat bone marrow, cells were infected with recombinant adenovirus vector Ad-let-7a. Lewis rats were subcutaneously injected with monocrotaline (MCT) to induce PAH, followed by the administration of MSCs, MSCs-NC (miR-control), or MSC-let-7a, respectively. Then, right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling were evaluated. Rat pulmonary artery smooth muscle cells (rPASMCs) under hypoxia were co-cultured with MSCs or MSC-let-7a. Cell proliferation and apoptosis were separately determined by
3 H thymidine incorporation and flow cytometry analysis. The underlying mechanism was also investigated., Results: MSC transplantation enhanced let-7a levels in MCT-induced PAH rats. After injection with MSC-let-7a, RVSP, right ventricular hypertrophy, and pulmonary vascular remodeling were notably ameliorated, indicating a protective effect of MSC-let-7a against PAH. When co-cultured with MSC-let-7a, hypoxia-triggered PASMC proliferation was obviously attenuated, concomitant with the decrease in cell proliferation-associated proteins. Simultaneously, the resistance of PASMCs to apoptosis was remarkably abrogated by MSC-let-7a administration. A mechanism assay revealed that MSC-let-7a restrained the activation of signal transducers and activators of transcription 3 (STAT3) and increased its downstream bone morphogenetic protein receptor 2 (BMPR2) expression. Importantly, preconditioning with BMPR2 siRNA dramatically abated the suppressive effects of MSC-let-7a on PASMC proliferation and apoptosis resistance., Conclusions: Collectively, this study suggests that MSCs modified with let-7a may ameliorate the progression of PAH by inhibiting PASMC growth through the STAT3-BMPR2 signaling, supporting a promising therapeutic strategy for PAH patients.- Published
- 2017
- Full Text
- View/download PDF