Document Detail


Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell-derived cardiomyocytes.
MedLine Citation:
PMID:  25227700     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
OBJECTIVE: Generating myocyte grafts that bridge across infarcts could maximize their functional impact and best utilize small numbers of stem cells. To date, however, graft survival within acute infarcts has not been feasible. To enhance intrainfarct graft viability, human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were pretreated before implantation with cobalt protoporphyrin (CoPP), a pharmacologic inducer of cytoprotective heme oxygenase-1.
METHODS: After preculturing with CoPP (vs phosphate-buffered saline), hESC-CMs were injected intramyocardially into acutely infarcted rat hearts, using directed injections to span the infarct. A further group received CoPP-pretreated hESC-CMs plus 4 weekly doses of systemic CoPP to prolong exposure to cytoprotectants. Two control groups with infarcts received vehicle-only intramyocardial injections or weekly systemic CoPP without cell therapy. Postinfarct ventricular function was gauged by echocardiography and graft size quantified at 8 weeks by histomorphometry.
RESULTS: CoPP-preconditioned hESC-CMs formed stable grafts deep within infarcted myocardium, while grafts without CoPP exposure survived mainly at the infarct periphery. Fractional shortening was improved at 4 and 8 weeks in all hearts receiving cell therapies (P < .01 vs vehicle-only injections). CoPP treatment of both graft hESC-CMs and recipient animals resulted in the largest grafts, highest fractional shortening, preserved wall thickness, and reduced infarct dimensions.
CONCLUSIONS: Cellular therapy delivered acutely after infarction significantly improved postinfarct ventricular function at 1 and 2 months. CoPP pretreatment of cells resulted in stable hESC-CM grafts within infarcted myocardium. This design enables construction of directionally oriented, infarct-spanning bands of new cardiomyocytes that might further improve functional restoration as engrafted myocytes proliferate and mature.
Authors:
Jun Luo; Matthew S Weaver; James E Dennis; Elizabeth Whalen; Michael A Laflamme; Margaret D Allen
Publication Detail:
Type:  Journal Article     Date:  2014-07-24
Journal Detail:
Title:  The Journal of thoracic and cardiovascular surgery     Volume:  148     ISSN:  1097-685X     ISO Abbreviation:  J. Thorac. Cardiovasc. Surg.     Publication Date:  2014 Dec 
Date Detail:
Created Date:  2014-12-01     Completed Date:  -     Revised Date:  2014-12-03    
Medline Journal Info:
Nlm Unique ID:  0376343     Medline TA:  J Thorac Cardiovasc Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3180-3188.e1     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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Descriptor/Qualifier:
Grant Support
ID/Acronym/Agency:
R01 HL064387/HL/NHLBI NIH HHS; R01 HL086709/HL/NHLBI NIH HHS

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