Document Detail


Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair.
MedLine Citation:
PMID:  22841153     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: The goal of this study was to demonstrate the enhancement of human cardiac progenitor cell (hCPC) reparative and regenerative potential by genetic modification for the treatment of myocardial infarction.
BACKGROUND: Regenerative potential of stem cells to repair acute infarction is limited. Improved hCPC survival, proliferation, and differentiation into functional myocardium will increase efficacy and advance translational implementation of cardiac regeneration.
METHODS: hCPCs isolated from the myocardium of heart failure patients undergoing left ventricular assist device implantation were engineered to express green fluorescent protein (hCPCe) or Pim-1-GFP (hCPCeP). Functional tests of hCPC regenerative potential were performed with immunocompromised mice by using intramyocardial adoptive transfer injection after infarction. Myocardial structure and function were monitored by echocardiographic and hemodynamic assessment for 20 weeks after delivery. hCPCe and hCPCeP expressing luciferase were observed by using bioluminescence imaging to noninvasively track persistence.
RESULTS: hCPCeP exhibited augmentation of reparative potential relative to hCPCe control cells, as shown by significantly increased proliferation coupled with amelioration of infarction injury and increased hemodynamic performance at 20 weeks post-transplantation. Concurrent with enhanced cardiac structure and function, hCPCeP demonstrated increased cellular engraftment and differentiation with improved vasculature and reduced infarct size. Enhanced persistence of hCPCeP versus hCPCe was revealed by bioluminescence imaging at up to 8 weeks post-delivery.
CONCLUSIONS: Genetic engineering of hCPCs with Pim-1 enhanced repair of damaged myocardium. Ex vivo gene delivery to modify stem cells has emerged as a viable option addressing current limitations in the field. This study demonstrates that efficacy of hCPCs from the failing myocardium can be safely and significantly enhanced through expression of Pim-1 kinase, setting the stage for use of engineered cells in pre-clinical settings.
Authors:
Sadia Mohsin; Mohsin Khan; Haruhiro Toko; Brandi Bailey; Christopher T Cottage; Kathleen Wallach; Divya Nag; Andrew Lee; Sailay Siddiqi; Feng Lan; Kimberlee M Fischer; Natalie Gude; Pearl Quijada; Daniele Avitabile; Silvia Truffa; Brett Collins; Walter Dembitsky; Joseph C Wu; Mark A Sussman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-26
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  60     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-28     Completed Date:  2012-12-18     Revised Date:  2013-10-17    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1278-87     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Affiliation:
SDSU Heart Research Institute, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation
Echocardiography
Gene Expression
Genetic Engineering*
Green Fluorescent Proteins / genetics,  metabolism
Hemodynamics
Humans
Luminescent Measurements
Mice
Myocardial Infarction / therapy*
Myocytes, Cardiac / enzymology,  transplantation*
Neovascularization, Pathologic
Proto-Oncogene Proteins c-pim-1 / genetics,  metabolism*
Stem Cell Transplantation
Stem Cells / enzymology
Grant Support
ID/Acronym/Agency:
P01 HL085577/HL/NHLBI NIH HHS; P01HL085577/HL/NHLBI NIH HHS; R01 HL067245/HL/NHLBI NIH HHS; R01 HL105759/HL/NHLBI NIH HHS; R01 HL113656/HL/NHLBI NIH HHS; R01 HL113656/HL/NHLBI NIH HHS; R01EB009689/EB/NIBIB NIH HHS; R01HL067245,/HL/NHLBI NIH HHS; R01HL105759/HL/NHLBI NIH HHS; R21 HL102613/HL/NHLBI NIH HHS; R21 HL102714/HL/NHLBI NIH HHS; R21 HL104544/HL/NHLBI NIH HHS; R21HL102613/HL/NHLBI NIH HHS; R21HL102714/HL/NHLBI NIH HHS; R21HL104544/HL/NHLBI NIH HHS; R37 HL091102/HL/NHLBI NIH HHS; R37HL091102/HL/NHLBI NIH HHS; RC1 HL100891/HL/NHLBI NIH HHS; RC1HL100891/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
147336-22-9/Green Fluorescent Proteins; EC 2.7.11.1/Proto-Oncogene Proteins c-pim-1
Comments/Corrections
Comment In:
J Am Coll Cardiol. 2012 Oct 2;60(14):1288-90   [PMID:  22841152 ]

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