title: Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction.
abstract: OBJECTIVE
  This study was designed to determine whether controlled release of basic fibroblast growth factor (bFGF) might improve human cardiosphere-derived cell (hCDC) therapy in a pig model of chronic myocardial infarction.
  
  
  BACKGROUND
  Current cell therapies for cardiac repair are limited by loss of the transplanted cells and poor differentiation.
  
  
  METHODS
  We conducted 2 randomized, placebo-controlled studies in immunosuppressed pigs with anterior myocardial infarctions. Four weeks after coronary reperfusion, 14 pigs were randomly assigned to receive an intramyocardial injection of placebo medium with or without bFGF-incorporating hydrogel implantation. As a second study, 26 pigs were randomized to receive controlled release of bFGF combined with or without hCDCs or bone marrow-derived mesenchymal stem cell transplantation 4 weeks after reperfusion.
  
  
  RESULTS
  Controlled release of bFGF in ischemic myocardium significantly augmented the formation of microvascular networks to enhance myocardial perfusion and contractile function. When combined with cell transplantation, the additive effects of bFGF were confined to hCDC-injected animals, but were not observed in animals receiving human bone marrow-derived mesenchymal stem cell transplantation. This was shown by increased donor-cell engraftment and enhanced cardiomyocyte differentiation in the transplanted hearts, resulting in synergistically improved ventricular function and regional wall motion and reduced infarct size.
  
  
  CONCLUSIONS
  Controlled delivery of bFGF modulates the post-ischemic microenvironment to enhance hCDC engraftment and differentiation. This novel strategy demonstrates significant functional improvements after myocardial infarction and may potentially represent a therapeutic approach to be studied in a clinical trial in human heart failure.
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Takehara
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tsutsumi
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tomosaburo
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Takamatsu
authors.affiliation: Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.affiliation: Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Komeda
authors.affiliation: Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yaku
authors.affiliation: Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. Electronic address: matsubah@koto.kpu-m.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan. Electronic address: hidemasa@kuhp.kyoto-u.ac.jp.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Oh
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D017690:Cell Transplantation / Q000379:methods*; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008954:Models, Biological; D009203:Myocardial Infarction / Q000628:therapy*; D015425:Myocardial Reperfusion; D010919:Placebos; D011897:Random Allocation; D015424:Reperfusion; D013552:Swine
chemical_list: D010919:Placebos; D016222:Fibroblast Growth Factor 2