title: Let-7a-transfected mesenchymal stem cells ameliorate monocrotaline-induced pulmonary hypertension by suppressing pulmonary artery smooth muscle cell growth through STAT3-BMPR2 signaling.
abstract: 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 by3H 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.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
authors.forename: Gesheng
authors.initials: G
authors.lastname: Cheng
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China. xingyewang1976@tom.com.
authors.forename: Xingye
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: He
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016686:Monocrotaline; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D016686:Monocrotaline; C498220:Bmpr2 protein, rat; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: BMPR2; Pulmonary arterial hypertension; STAT3 pathway; let-7a; mesenchymal stem cells; pulmonary artery smooth muscle cell