Document Detail


Activation of diverse signaling pathways by ex-vivo delivery of multiple cytokines for myocardial repair.
MedLine Citation:
PMID:  22873203     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We tested the hypothesis that simultaneous transgenic overexpression of a select quartet of growth factors activates diverse signaling pathways for mobilization and participation of various stem/progenitor cells for cardiogenesis in the infarcted heart. Human insulin growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 (SDF-1a), and hepatocyte growth factor (HGF) plasmids were synthesized and transfected into skeletal myoblasts (SM) from young male wild-type or transgenic rats expressing green fluorescent protein (GFP). Overexpression of growth factors in transfected SM ((Trans)SM) was confirmed by reverse transcription polymerase chain reaction, western blotting, and fluorescence immunostaining. Using our custom-made growth factor array and western blotting, multiple angiogenic and prosurvival factors were detected in (Trans)SM, including secreted frizzled related protein-1,2,4,5, matrix metalloproteinases-3 and 9, connexin-43, netrin-1, Nos-2, Wnt-3, Akt, MAPK42/44, Stat3, nuclear factor kappa B (NFκB), hypoxia-inducible factor 1 (HIF-1α), and protein kinase C (PKC). The conditioned medium (CM) from (Trans)SM was cytoprotective for cardiomyocytes following H(2)O(2) treatment [P<0.01 vs. CM from native SM ((Nat)SM)], promoted a higher transwell migration of human umbilical cord vein endothelial cells (223.3±1.8, P<0.01) and in vitro tube formation (47.8±1.9, P<0.01). Intramyocardial transplantation of 1.5×10(6) (Trans)SM (group-3) in a rat model of acute myocardial infarction induced extensive mobilization of cMet(+), ckit(+), ckit(+)/GATA(4+), CXCR4(+), CD44(+), CD31(+), and CD59(+) cells into the infarcted heart on day 7 and improved integration of (Trans)SM in the heart compared to (Nat)SM (group 2) (P<0.05). Extensive neomyogenesis and angiogenesis in group-3 (P<0.01 vs. group-2), with resultant attenuation of infarct size (P<0.01 vs. group-2) and improvement in global heart function (P<0.01 vs. group-2) was observed at 8 weeks. In conclusion, simultaneous activation of diverse signaling pathways by overexpression of multiple growth factors caused massive mobilization and homing of stem/progenitor cells from peripheral circulation, the bone marrow, and the heart for accelerated repair of the infarcted myocardium.
Authors:
Mikhail Konoplyannikov; Khawaja Husnain Haider; Vien Khach Lai; Rafeeq P H Ahmed; Shujia Jiang; Muhammad Ashraf
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-05
Journal Detail:
Title:  Stem cells and development     Volume:  22     ISSN:  1557-8534     ISO Abbreviation:  Stem Cells Dev.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-11     Completed Date:  2013-07-02     Revised Date:  2014-01-26    
Medline Journal Info:
Nlm Unique ID:  101197107     Medline TA:  Stem Cells Dev     Country:  United States    
Other Details:
Languages:  eng     Pagination:  204-15     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Cell Movement / drug effects
Cells, Cultured
Chemokine CXCL12 / genetics,  metabolism
Culture Media, Conditioned / metabolism,  pharmacology
Cytoprotection
Female
Gap Junctions / drug effects,  metabolism
Green Fluorescent Proteins / metabolism
Heart Function Tests / methods
Heart Ventricles / drug effects,  metabolism,  pathology
Hepatocyte Growth Factor / genetics,  metabolism*
Human Umbilical Vein Endothelial Cells / drug effects,  metabolism
Humans
Hydrogen Peroxide / pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit / genetics,  metabolism
Immunohistochemistry
In Situ Nick-End Labeling
Insulin-Like Growth Factor I / genetics,  metabolism
Male
Muscle Development
Myoblasts, Skeletal / metabolism,  transplantation
Myocardial Infarction / metabolism,  pathology,  therapy*
Myocytes, Cardiac / drug effects,  metabolism
Plasmids / genetics,  metabolism
Rats
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction*
Transfection / methods*
Vascular Endothelial Growth Factor A / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
HL-087288/HL/NHLBI NIH HHS; HL-089535/HL/NHLBI NIH HHS; HL080686/HL/NHLBI NIH HHS; HL087246/HL/NHLBI NIH HHS; R37-HL074272/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/CXCL12 protein, human; 0/Chemokine CXCL12; 0/Culture Media, Conditioned; 0/HGF protein, human; 0/Hif1a protein, rat; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; 147336-22-9/Green Fluorescent Proteins; 67256-21-7/Hepatocyte Growth Factor; 67763-96-6/Insulin-Like Growth Factor I; BBX060AN9V/Hydrogen Peroxide
Comments/Corrections

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