Document Detail


Myocardial injection with GSK-3β-overexpressing bone marrow-derived mesenchymal stem cells attenuates cardiac dysfunction after myocardial infarction.
MedLine Citation:
PMID:  21233455     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: 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).
METHODS AND 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:
Jaeyeaon Cho; Peiyong Zhai; Yasuhiro Maejima; Junichi Sadoshima
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-13
Journal Detail:
Title:  Circulation research     Volume:  108     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-21     Completed Date:  2011-04-11     Revised Date:  2013-07-02    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  478-89     Citation Subset:  IM    
Affiliation:
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Marrow Cells / cytology,  metabolism
Cell Differentiation / physiology
Disease Models, Animal
Glycogen Synthase Kinase 3 / genetics,  metabolism*
Hypertrophy, Left Ventricular / etiology*,  pathology,  prevention & control*
Injections
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stromal Cells / cytology,  metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardial Infarction / complications*
Myocytes, Cardiac / cytology,  physiology
Signal Transduction / physiology
Tissue Therapy / methods*
Ventricular Remodeling
Grant Support
ID/Acronym/Agency:
AG23039/AG/NIA NIH HHS; AG27211/AG/NIA NIH HHS; HL102738/HL/NHLBI NIH HHS; HL59139/HL/NHLBI NIH HHS; HL67724/HL/NHLBI NIH HHS; HL69020/HL/NHLBI NIH HHS; HL91469/HL/NHLBI NIH HHS; R01 AG023039-01/AG/NIA NIH HHS; R01 AG023039-02/AG/NIA NIH HHS; R01 AG023039-03/AG/NIA NIH HHS; R01 AG023039-04/AG/NIA NIH HHS; R01 AG023039-05/AG/NIA NIH HHS; R01 AG023039-06/AG/NIA NIH HHS; R01 AG023039-06S1/AG/NIA NIH HHS; R01 AG023039-07/AG/NIA NIH HHS; R01 AG023039-08/AG/NIA NIH HHS; R01 AG023039-09/AG/NIA NIH HHS; R01 AG028787-01/AG/NIA NIH HHS; R01 HL067724-01/HL/NHLBI NIH HHS; R01 HL067724-02/HL/NHLBI NIH HHS; R01 HL067724-03/HL/NHLBI NIH HHS; R01 HL067724-04/HL/NHLBI NIH HHS; R01 HL067724-05/HL/NHLBI NIH HHS; R01 HL067724-06/HL/NHLBI NIH HHS; R01 HL067724-07/HL/NHLBI NIH HHS; R01 HL067724-08/HL/NHLBI NIH HHS; R01 HL067724-09/HL/NHLBI NIH HHS; R01 HL067724-10/HL/NHLBI NIH HHS; R01 HL067724-11/HL/NHLBI NIH HHS; R01 HL067724-12/HL/NHLBI NIH HHS; R01 HL067727-01/HL/NHLBI NIH HHS; R01 HL091469-01/HL/NHLBI NIH HHS; R01 HL091469-02/HL/NHLBI NIH HHS; R01 HL091469-02W1/HL/NHLBI NIH HHS; R01 HL091469-03/HL/NHLBI NIH HHS; R01 HL091469-04/HL/NHLBI NIH HHS; R01 HL091469-05/HL/NHLBI NIH HHS; R01 HL102738-01/HL/NHLBI NIH HHS; R01 HL102738-02/HL/NHLBI NIH HHS; R01 HL102738-03/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3
Comments/Corrections

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