Let-7a-transfected mesenchymal stem cells ameliorate monocrotaline-induced pulmonary hypertension by suppressing pulmonary artery smooth muscle cell growth through STAT3-BMPR2 signaling

• Published in: Stem cell research & therapy Vol. 8; no. 1; p. 34
• Main Authors: Cheng, Gesheng, Wang, Xingye, Li, Yongxin, He, Lu
• Format: Journal Article
• Language: English
• Published: England BioMed Central 10.02.2017
• Subjects: Adenoviridae; Adenoviridae - genetics; Adenoviridae - metabolism; Animals; Bone Morphogenetic Protein Receptors, Type II - genetics; 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; Hypertension, Pulmonary - therapy; Hypertrophy, Right Ventricular - chemically induced; Hypertrophy, Right Ventricular - pathology; Hypertrophy, Right Ventricular - physiopathology; Hypertrophy, Right Ventricular - therapy; Lung - blood supply; Lung - pathology; Lung - physiopathology; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; MicroRNAs - genetics; 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; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transfection; STAT3 pathway; Pulmonary arterial hypertension; BMPR2; let-7a; pulmonary artery smooth muscle cell; mesenchymal stem cells
• ISSN: 1757-6512; 1757-6512
• DOI: 10.1186/s13287-017-0480-y

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. 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 H thymidine incorporation and flow cytometry analysis. The underlying mechanism was also investigated. 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. 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.