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CXCR4 Antagonist TG-0054 Mobilizes Mesenchymal Stem Cells, Attenuates Inflammation, and Preserves Cardiac Systolic Function in a Porcine Model of Myocardial Infarction.
MedLine Citation:
PMID:  24823505     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Interaction between chemokine stromal-cell-derived factor 1 (SDF-1) and the CXC chemokine receptor 4 (CXCR4) governs the sequestration and mobilization of bone marrow stem cells. We investigated the therapeutic potential of TG-0054, a novel CXCR4 antagonist, in attenuating cardiac dysfunction after myocardial infarction (MI). In miniature pigs (minipigs), TG-0054 mobilized CD34(+)CXCR4(+), CD133(+)CXCR4(+), and CD271(+)CXCR4(+) cells into peripheral circulation. After isolation and expansion, TG-0054-mobilized CD271(+) cells were confirmed as mesenchyaml stem cells (designated CD271-MSCs) by assessing the tri-lineage differentiation potential, surface markers, and immunosuppressive effects on allogeneic lymphocyte proliferation. MI was induced in 22 minipigs using balloon occlusion of the left anterior descending coronary artery, followed by intravenous injections of 2.85 mg/kg of TG-0054 (n = 12) or saline (n = 10) at 3 d and 7 d post-MI. Serial magnetic resonance imaging analyses revealed that TG-0054-treatment prevented left ventricular (LV) dysfunction at 12 wk after MI (change of LV ejection fraction from baseline, -1.0 ± 6.2% in the TG-0054 group, vs. -7.9 ± 5.8% in the controls, p = 0.014). The preserved cardiac function was accompanied by a significant decrease in the myocardial expression of TNF-α, IL-1β, and IL-6 at 7 d post-MI. Moreover, the plasma levels of TNF-α, IL-1β, and IL-6 were persistently suppressed by the TG-0054 treatment. Infusion of TG-0054-mobilized-CD271-MSCs reduced both myocardial and plasma cytokine levels in a pattern which is temporally correlated with TG-0054 treatment. This study demonstrated that TG-0054 improves the impaired LV contractility following MI, at least in part, by mobilizing MSCs to attenuate the post-infarction inflammation. This insight may facilitate exploring novel stem cell-based therapy for treating post-MI heart failure.
Authors:
Wan-Tseng Hsu; Hsiang-Yiang Jui; Ying-Huey Huang; Mao-Yuan M Su; Yen-Wen Wu; Wen-Yih I Tseng; Ming-Chu Hsu; Bor-Luen Chiang; Kenneth K Wu; Chii-Ming Lee
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-5-12
Journal Detail:
Title:  Cell transplantation     Volume:  -     ISSN:  1555-3892     ISO Abbreviation:  Cell Transplant     Publication Date:  2014 May 
Date Detail:
Created Date:  2014-5-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9208854     Medline TA:  Cell Transplant     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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