title: Hepatocyte growth factor modification enhances the anti-arrhythmic properties of human bone marrow-derived mesenchymal stem cells.
abstract: OBJECTIVE
  Chronic myocardial infarction (MI) results in the formation of arrhythmogenic substrates, causing lethal ventricular arrhythmia (VA). We aimed to determine whether mesenchymal stem cells (MSCs) carrying a hepatocyte growth factor (HGF) gene modification (HGF-MSCs) decrease the levels of arrhythmogenic substrates and reduce the susceptibility to developing VA compared with unmodified MSCs and PBS in a swine infarction model.
  
  
  METHODS
  The left descending anterior artery was balloon-occluded to establish an MI model. Four weeks later, the randomly grouped pigs were administered MSCs, PBS or HGF-MSCs via thoracotomy. After an additional four weeks, dynamic electrocardiography was performed to assess heart rate variability, and programmed electrical stimulation was conducted to evaluate the risk for VA. Then, the pigs were euthanized for morphometric, immunofluorescence and western blot analyses.
  
  
  RESULTS
  The HGF-MSC group displayed the highest vessel density and Cx43 expression levels, and the lowest levels of apoptosis, and tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) expression. Moreover, the HGF-MSC group exhibited a decrease in the number of sympathetic nerve fibers, substantial decreases in the low frequency and the low-/high- frequency ratio and increases in the root mean square of successive differences (rMSSD) and the percentage of successive normal sinus R-R intervals longer than 50 ms (pNN50), compared with the other two groups. Finally, the HGF-MSC group displayed the lowest susceptibility to developing VA.
  
  
  CONCLUSIONS
  HGF-MSCs displayed potent antiarrhythmic effects, reducing the risk for VA.
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Wang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: Department of Cardiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Yu
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Wei-Zhu
authors.initials: WZ
authors.lastname: Ju
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Man
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Xiao-Rong
authors.initials: XR
authors.lastname: Li
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Zi-Dun
authors.initials: ZD
authors.lastname: Wang
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Wei-Juan
authors.initials: WJ
authors.lastname: Gu
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Feng-Xiang
authors.initials: FX
authors.lastname: Zhang
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China.
authors.forename: Chu-Tse
authors.initials: CT
authors.lastname: Wu
authors.affiliation: Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Ke-Jiang
authors.initials: KJ
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001145:Arrhythmias, Cardiac / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D001341:Autonomic Nervous System / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000166:cytology*; D002470:Cell Survival; D004558:Electric Stimulation; D005786:Gene Expression Regulation; D006352:Heart Ventricles / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D018919:Neovascularization, Physiologic; D013552:Swine
chemical_list: D017228:Hepatocyte Growth Factor