title: Hypoxia preconditioned mesenchymal stem cells prevent cardiac fibroblast activation and collagen production via leptin.
abstract: OBJECTIVE
  Activation of cardiac fibroblasts into myofibroblasts constitutes a key step in cardiac remodeling after myocardial infarction (MI), due to interstitial fibrosis. Mesenchymal stem cells (MSCs) have been shown to improve post-MI remodeling an effect that is enhanced by hypoxia preconditioning (HPC). Leptin has been shown to promote cardiac fibrosis. The expression of leptin is significantly increased in MSCs after HPC but it is unknown whether leptin contributes to MSC therapy or the fibrosis process. The objective of this study was to determine whether leptin secreted from MSCs modulates cardiac fibrosis.
  
  
  METHODS
  Cardiac fibroblast (CF) activation was induced by hypoxia (0.5% O2). The effects of MSCs on fibroblast activation were analyzed by co-culturing MSCs with CFs, and detecting the expression of α-SMA, SM22α, and collagen IαI in CFs by western blot, immunofluorescence and Sirius red staining. In vivo MSCs antifibrotic effects on left ventricular remodeling were investigated using an acute MI model involving permanent ligation of the left anterior descending coronary artery.
  
  
  RESULTS
  Co-cultured MSCs decreased fibroblast activation and HPC enhanced the effects. Leptin deficit MSCs from Ob/Ob mice did not decrease fibroblast activation. Consistent with this, H-MSCs significantly inhibited cardiac fibrosis after MI and mediated decreased expression of TGF-β/Smad2 and MRTF-A in CFs. These effects were again absent in leptin-deficient MSCs.
  
  
  CONCLUSIONS
  Our data demonstrate that activation of cardiac fibroblast was inhibited by MSCs in a manner that was leptin-dependent. The mechanism may involve blocking TGF-β/Smad2 and MRTF-A signal pathways.
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Yinchuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Zhaocai
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
authors.affiliation: Division of Cardiology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Province, Hangzhou, China; Provincial Key Laboratory of Cardiovascular Research, Zhejiang Province, Hangzhou, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003094:Collagen / Q000096:biosynthesis*; D015870:Gene Expression; D000860:Hypoxia / Q000378:metabolism*; D019157:Ischemic Preconditioning, Myocardial; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D020738:Leptin; C511173:Mrtfa protein, mouse; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D003094:Collagen