title: Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell-derived cardiomyocytes.
abstract: 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.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Jun
authors.initials: J
authors.lastname: Luo
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Weaver
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: James E
authors.initials: JE
authors.lastname: Dennis
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Whalen
authors.affiliation: University of Washington School of Medicine, Seattle, Wash.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
authors.affiliation: Benaroya Research Institute at Virginia Mason, Seattle, Wash; University of Washington School of Medicine, Seattle, Wash. Electronic address: mallen@benaroyaresearch.org.
authors.forename: Margaret D
authors.initials: MD
authors.lastname: Allen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000637:transplantation*; D006085:Graft Survival / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D011524:Protoporphyrins / Q000494:pharmacology*; D011923:Rats, Nude; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation; D016276:Ventricular Function / Q000187:drug effects*
chemical_list: D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat