Jun Luo1, Matthew S Weaver1, James E Dennis1, Elizabeth Whalen1, Michael A Laflamme2, Margaret D Allen3. 1. Benaroya Research Institute at Virginia Mason, Seattle, Wash. 2. University of Washington School of Medicine, Seattle, Wash. 3. Benaroya Research Institute at Virginia Mason, Seattle, Wash; University of Washington School of Medicine, Seattle, Wash. Electronic address: mallen@benaroyaresearch.org.
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.
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 infarctedrat 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: Juan C Chachques; Barbara Cattadori; Jesus Herreros; Felipe Prosper; Jorge C Trainini; Didier Blanchard; Jean-Noël Fabiani; Alain Carpentier Journal: Herz Date: 2002-11 Impact factor: 1.443
Authors: Luis G Melo; Reitu Agrawal; Lunan Zhang; Mojgan Rezvani; Abeel A Mangi; Afshin Ehsan; Daniel P Griese; Giorgio Dell'Acqua; Michael J Mann; Junichi Oyama; Shaw-Fang Yet; Matthew D Layne; Mark A Perrella; Victor J Dzau Journal: Circulation Date: 2002-02-05 Impact factor: 29.690
Authors: S F Yet; R Tian; M D Layne; Z Y Wang; K Maemura; M Solovyeva; B Ith; L G Melo; L Zhang; J S Ingwall; V J Dzau; M E Lee; M A Perrella Journal: Circ Res Date: 2001-07-20 Impact factor: 17.367
Authors: Yorihiro Akamatsu; Manabu Haga; Shivraj Tyagi; Kenichiro Yamashita; Aurelio Vicente Graça-Souza; Robert Ollinger; Eva Czismadia; G Aaron May; Emeka Ifedigbo; Leo E Otterbein; Fritz H Bach; Miguel P Soares Journal: FASEB J Date: 2004-02-20 Impact factor: 5.191
Authors: M A Pfeffer; J M Pfeffer; M C Fishbein; P J Fletcher; J Spadaro; R A Kloner; E Braunwald Journal: Circ Res Date: 1979-04 Impact factor: 17.367
Authors: Ann C Gaffey; Minna H Chen; Chantel M Venkataraman; Alen Trubelja; Christopher B Rodell; Patrick V Dinh; George Hung; John W MacArthur; Renganaden V Soopan; Jason A Burdick; Pavan Atluri Journal: J Thorac Cardiovasc Surg Date: 2015-07-17 Impact factor: 5.209