Naofumi Takehara1, Yoshiaki Tsutsumi2, Kento Tateishi3, Takehiro Ogata1, Hideo Tanaka4, Tomomi Ueyama1, Tomosaburo Takahashi3, Tetsuro Takamatsu4, Masanori Fukushima5, Masashi Komeda6, Masaaki Yamagishi7, Hitoshi Yaku7, Yasuhiko Tabata8, Hiroaki Matsubara9, Hidemasa Oh10. 1. Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan. 2. Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 3. Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan; Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 4. Department of Pathology and Cell Regulation, Kyoto Prefectural University of Medicine, Kyoto, Japan. 5. Division of Clinical Trial Design and Management, Translational Research Center, Kyoto University, Kyoto, Japan. 6. Department of Cardiovascular Surgery, Toyohashi Heart Center, Toyohashi, Japan. 7. Department of Cardiovascular Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. 8. Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan. 9. 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. 10. Department of Experimental Therapeutics, Translational Research Center, Kyoto University, Kyoto, Japan. Electronic address: hidemasa@kuhp.kyoto-u.ac.jp.
Abstract
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.
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 humanheart failure.