Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction.
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.
Takehara
Naofumi
N
Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan.
Tsutsumi
Yoshiaki
Y
Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tateishi
Kento
K
Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Ogata
Takehiro
T
Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan.
Tanaka
Hideo
H
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Ueyama
Tomomi
T
Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan.
Takahashi
Tomosaburo
T
Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Takamatsu
Tetsuro
T
Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Fukushima
Masanori
M
Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University, Kyoto, Japan.
Komeda
Masashi
M
Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan.
Yamagishi
Masaaki
M
Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Yaku
Hitoshi
H
Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tabata
Yasuhiko
Y
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
Matsubara
Hiroaki
H
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.
Oh
Hidemasa
H
Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan. Electronic address: hidemasa@kuhp.kyoto-u.ac.jp.
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
D010919:Placebos; D016222:Fibroblast Growth Factor 2