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MINI-FOCUS: CELL-BASED THERAPY

Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction

Naofumi Takehara, MD, PhD^_*, Yoshiaki Tsutsumi, MD, PhD^||, Kento Tateishi, MD, PhD^_*,||, Takehiro Ogata, MD, PhD^_*, Hideo Tanaka, MD, PhD^¶, Tomomi Ueyama, MD, PhD^_*, Tomosaburo Takahashi, MD, PhD^_*,||, Tetsuro Takamatsu, MD, PhD^¶, Masanori Fukushima, MD, PhD, Masashi Komeda, MD, PhD, Masaaki Yamagishi, MD, PhD^#, Hitoshi Yaku, MD, PhD^#, Yasuhiko Tabata, PhD, DMedSci, Dpharm, Hiroaki Matsubara, MD, PhD^_*,||,_* and Hidemasa Oh, MD, PhD^_*,_*

^_* Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan
Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University, Kyoto, Japan
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan
^|| Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
^¶ Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan
^# Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

Manuscript received March 7, 2008; revised manuscript received June 4, 2008, accepted June 10, 2008.

^_* Reprint requests and correspondence: Dr. Hidemasa Oh or Dr. Hiroaki Matsubara, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan (Email: matsubah{at}koto.kpu-m.ac.jp).

Objectives: 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.

Key Words: cell therapy • bFGF • gelatin hydrogel • heart failure • myocardial infarction

Abbreviations and Acronyms   bFGF = basic fibroblast growth factor   DMEM = Dulbecco's Modified Eagle Medium   FISH = fluorescent in situ hybridization   hBMC = human bone marrow–derived mesenchymal stem cell   hCDC = human cardiosphere-derived cell   LV = left ventricle/ventricular   LVEF = left ventricular ejection fraction   MRI = magnetic resonance imaging   SPIO = superparamagnetic iron oxide   SRS = systolic radial strain

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