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

Naofumi Takehara, Yoshiaki Tsutsumi, Kento Tateishi, Takehiro Ogata, Hideo Tanaka, Tomomi Ueyama, Tomosaburo Takahashi, Tetsuro Takamatsu, Masanori Fukushima, Masashi Komeda, Masaaki Yamagishi, Hitoshi Yaku, Yasuhiko Tabata, Hiroaki Matsubara, Hidemasa Oh

Research output: Contribution to journalArticle

162 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1858-1865
Number of pages8
JournalJournal of the American College of Cardiology
Volume52
Issue number23
DOIs
Publication statusPublished - Dec 2 2008
Externally publishedYes

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Fibroblast Growth Factor 2
Myocardial Infarction
Swine
Mesenchymal Stem Cell Transplantation
Cell- and Tissue-Based Therapy
Cell Differentiation
Bone Marrow
Placebos
Myocardial Reperfusion
Ventricular Function
Hydrogel
Cell Transplantation
Microvessels
Cardiac Myocytes
Reperfusion
Myocardium
Heart Failure
Perfusion
Clinical Trials
Injections

Keywords

  • bFGF
  • cell therapy
  • gelatin hydrogel
  • heart failure
  • myocardial infarction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction. / Takehara, Naofumi; Tsutsumi, Yoshiaki; Tateishi, Kento; Ogata, Takehiro; Tanaka, Hideo; Ueyama, Tomomi; Takahashi, Tomosaburo; Takamatsu, Tetsuro; Fukushima, Masanori; Komeda, Masashi; Yamagishi, Masaaki; Yaku, Hitoshi; Tabata, Yasuhiko; Matsubara, Hiroaki; Oh, Hidemasa.

In: Journal of the American College of Cardiology, Vol. 52, No. 23, 02.12.2008, p. 1858-1865.

Research output: Contribution to journalArticle

Takehara, N, Tsutsumi, Y, Tateishi, K, Ogata, T, Tanaka, H, Ueyama, T, Takahashi, T, Takamatsu, T, Fukushima, M, Komeda, M, Yamagishi, M, Yaku, H, Tabata, Y, Matsubara, H & Oh, H 2008, 'Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction', Journal of the American College of Cardiology, vol. 52, no. 23, pp. 1858-1865. https://doi.org/10.1016/j.jacc.2008.06.052
Takehara, Naofumi ; Tsutsumi, Yoshiaki ; Tateishi, Kento ; Ogata, Takehiro ; Tanaka, Hideo ; Ueyama, Tomomi ; Takahashi, Tomosaburo ; Takamatsu, Tetsuro ; Fukushima, Masanori ; Komeda, Masashi ; Yamagishi, Masaaki ; Yaku, Hitoshi ; Tabata, Yasuhiko ; Matsubara, Hiroaki ; Oh, Hidemasa. / Controlled Delivery of Basic Fibroblast Growth Factor Promotes Human Cardiosphere-Derived Cell Engraftment to Enhance Cardiac Repair for Chronic Myocardial Infarction. In: Journal of the American College of Cardiology. 2008 ; Vol. 52, No. 23. pp. 1858-1865.
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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.",
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AU - Takehara, Naofumi

AU - Tsutsumi, Yoshiaki

AU - Tateishi, Kento

AU - Ogata, Takehiro

AU - Tanaka, Hideo

AU - Ueyama, Tomomi

AU - Takahashi, Tomosaburo

AU - Takamatsu, Tetsuro

AU - Fukushima, Masanori

AU - Komeda, Masashi

AU - Yamagishi, Masaaki

AU - Yaku, Hitoshi

AU - Tabata, Yasuhiko

AU - Matsubara, Hiroaki

AU - Oh, Hidemasa

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N2 - 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.

AB - 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.

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