Enhanced therapeutic effects of mesenchymal stem cells on myocardial infarction by ischemic postconditioning through paracrine mechanisms in rats

J Mol Cell Cardiol. 2011 Nov;51(5):839-47. doi: 10.1016/j.yjmcc.2011.06.013. Epub 2011 Jun 29.

Abstract

Ischemic postconditioning (IPC) is cardioprotective against ischemia-reperfusion injury which impairs the myocardial micro-environment and reduces the survival of transplanted cells. We tested the hypothesis that IPC may improve the survival of transplanted cells and enhance their therapeutic effects. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) from Sprague-Dawley rats were infected with lentivirus carrying green fluorescent protein (GFP) gene. The left main coronary arteries of rats were occluded for a 30-min ischemia, followed by a 72 h or 28 d reperfusion. IPC was induced by 3 cycles of 10s reperfusion and 10s ischemia before sustained reperfusion. GFP-BMSCs were intramyocardially injected at 2h reperfusion. At 70 h after transplantation, IPC treatment increased the level of interleukin-10, B-cell leukemia-lymphoma-2 (BCL-2), and vascular endothelial and basic fibroblast growth factor (VEGF and bFGF), and decreased the level of tumor necrosis factor-α, interleukin-1β and BCL-2-associated X protein by ELISA or PCR or western blotting. The BMSCs therapy with IPC produced more surviving GFP-positive cells than the BMSCs therapy alone by fluorescent staining [at 70 h, (90 ± 14)/mm(2) vs. (61 ± 12)/mm(2), and at 28 days, (55 ± 14)/mm(2) vs. (26 ± 8)/mm(2), P<0.01, respectively]. At 28 days, it, when compared with the Control, IPC treatment, and BMSCs therapy, demonstrated higher left ventricular ejection fraction by echocardiography (62%± 8%, 69%± 6%, and 75%± 4% vs. 82%± 4%, P<0.05, respectively), higher expression of VEGF and bFGF by western blotting and PCR, less myocardial fibrosis by Masson's trichrome staining, and higher capillary density by immunohistochemistry. These results suggest that ischemic postconditioning promotes the survival of transplanted cells and enhances their repair of infarcted myocardium through paracrine mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Echocardiography
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Ischemic Postconditioning / methods*
  • Lentivirus
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Myocardial Infarction / diagnostic imaging
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Neovascularization, Physiologic
  • Paracrine Communication / genetics*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / diagnostic imaging
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / therapy
  • Transfection
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Interleukin-1beta
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Interleukin-10
  • Green Fluorescent Proteins