title: Myocardial injection with GSK-3β-overexpressing bone marrow-derived mesenchymal stem cells attenuates cardiac dysfunction after myocardial infarction.
abstract: BACKGROUND
  Glycogen synthase kinase (GSK)-3β upregulates cardiac genes in bone marrow-derived mesenchymal stem cells (MSCs) in vitro. Ex vivo modification of signaling mechanisms in MSCs may improve the efficiency of cardiac cell-based therapy (CBT).
  
  
  OBJECTIVE
  To test the effect of GSK-3β on the efficiency of CBT with MSCs after myocardial infarction (MI).
  
  
  RESULTS
  MSCs overexpressing either GSK-3β (GSK-3β-MSCs), LacZ (LacZ-MSCs), or saline was injected into the heart after coronary ligation. A significant improvement in the mortality and left ventricular (LV) function was observed at 12 weeks in GSK-3β-MSC-injected mice compared with in LacZ-MSC- or saline-injected mice. MI size and LV remodeling were reduced in GSK-3β-MSC-injected mice compared with in LacZ-MSC- or saline-injected ones. GSK-3β increased survival and increased cardiomyocyte differentiation of MSCs, as evidenced by activation of an Nkx2.5-LacZ reporter and upregulation of troponin T. Injection of GSK-3β-MSCs induced Ki67-positive myocytes and c-Kit-positive cells, suggesting that GSK-3β-MSCs upregulate cardiac progenitor cells. GSK-3β-MSCs also increased capillary density and upregulated paracrine factors, including vascular endothelial growth factor A (Vegfa). Injection of GSK-3β-MSCs in which Vegfa had been knocked down abolished the increase in survival and capillary density. However, the decrease in MI size and LV remodeling and the improvement of LV function were still observed in MI mice injected with GSK-3β-MSCs without Vegfa.
  
  
  CONCLUSIONS
  GSK-3β significantly improves the efficiency of CBT with MSCs in the post-MI heart. GSK-3β not only increases survival of MSCs but also induces cardiomyocyte differentiation and angiogenesis through Vegfa-dependent and -independent mechanisms.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Jaeyeaon
authors.initials: J
authors.lastname: Cho
authors.forename: Peiyong
authors.initials: P
authors.lastname: Zhai
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Junichi
authors.initials: J
authors.lastname: Sadoshima
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D007267:Injections; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000150:complications*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D020257:Ventricular Remodeling
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3