Hepatocyte growth factor modification enhances the anti-arrhythmic properties of human bone marrow-derived mesenchymal stem cells

PLoS One. 2014 Oct 31;9(10):e111246. doi: 10.1371/journal.pone.0111246. eCollection 2014.

Abstract

Background/aims: 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.

Conclusion: HGF-MSCs displayed potent antiarrhythmic effects, reducing the risk for VA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / therapy*
  • Autonomic Nervous System / physiopathology
  • Bone Marrow Cells / cytology*
  • Cell Survival
  • Electric Stimulation
  • Gene Expression Regulation
  • Heart Ventricles / physiopathology
  • Hepatocyte Growth Factor / genetics*
  • Humans
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology*
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy
  • Neovascularization, Physiologic
  • Swine

Substances

  • Hepatocyte Growth Factor

Grants and funding

This study was supported by grants from the National Natural Science Foundation of China (Grant No. 81170157, 81170160, 81470456), Six Peak Talents Foundation of Jiangsu Province (Grant No. 2011-WS-071), the Graduate Innovation Foundation of Jiangsu Province (Grant No. CXZZ 12_0568, JX22013218). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.