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(Circulation. 2009;120:S247-S254.)
© 2009 American Heart Association, Inc.

Cell Transplantation and Tissue Regeneration

Hepatocyte Growth Factor or Vascular Endothelial Growth Factor Gene Transfer Maximizes Mesenchymal Stem Cell–Based Myocardial Salvage After Acute Myocardial Infarction

Tobias Deuse, MD, PhD; Christoph Peter, PhD; Paul W.M. Fedak, MD; Tim Doyle, PhD; Hermann Reichenspurner, MD, PhD; Wolfram H. Zimmermann, MD, PhD; Thomas Eschenhagen, MD, PhD; William Stein, MD; Joseph C. Wu, MD, PhD; Robert C. Robbins, MD; Sonja Schrepfer, MD, PhD

From the Departments of Cardiothoracic Surgery (T.D., W.S., R.C.R., S.S.) and Cardiovascular Medicine (C.P., J.C.W.), and Pediatrics (T.D.), Stanford University, Stanford, Calif; Libin Cardiovascular Institute of Alberta (P.W.M.F.), Cardiac Science, University of Calgary, Canada; and the University Heart Center (H.R., T.D., S.S.) and Department of Pharmacology (W.H.Z., T.E.), University Hospital Hamburg, Germany.

Correspondence to Sonja Schrepfer, MD, PhD, Cardiothoracic Surgery, Stanford University, 300 Pasteur Drive, CVRB, Stanford CA 94305-5407. E-mail schrepfer{at}stanford.edu

Background— Mesenchymal stem cell (MSC)-based regenerative strategies were investigated to treat acute myocardial infarction and improve left ventricular function.

Methods and Results— Murine AMI was induced by coronary ligation with subsequent injection of MSCs, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), or MSCs +HGF/VEGF into the border zone. Left ventricular ejection fraction was calculated using micro–computed tomography imaging after 6 months. HGF and VEGF protein injection (with or without concomitant MSC injection) significantly and similarly improved the left ventricular ejection fraction and reduced scar size compared with the MSC group, suggesting that myocardial recovery was due to the cytokines rather than myocardial regeneration. To provide sustained paracrine effects, HGF or VEGF overexpressing MSCs were generated (MSC-HGF, MSC-VEGF). MSC-HGF and MSC-VEGF showed significantly increased in vitro proliferation and increased in vivo proliferation within the border zone. Cytokine production correlated with MSC survival. MSC-HGF– and MSC-VEGF–treated animals showed smaller scar sizes, increased peri-infarct vessel densities, and better preserved left ventricular function when compared with MSCs transfected with empty vector. Murine cardiomyocytes were exposed to hypoxic in vitro conditions. The LDH release was reduced, fewer cardiomyocytes were apoptotic, and Akt activity was increased if cardiomyocytes were maintained in conditioned medium obtained from MSC-HGF or MSC-VEGF cultures.

Conclusions— This study showed that (1) elevating the tissue levels of HGF and VEGF after acute myocardial infarction seems to be a promising reparative therapeutic approach, (2) HGF and VEGF are cardioprotective by increasing the tolerance of cardiomyocytes to ischemia, reducing cardiomyocyte apoptosis and increasing prosurvival Akt activation, and (3) MSC-HGF and MSC-VEGF are a valuable source for increased cytokine production and maximize the beneficial effect of MSC-based repair strategies.

Key Words: apoptosis • gene therapy • myocardial infarction • remodeling