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Am J Physiol Heart Circ Physiol 291: H886-H893, 2006. First published April 7, 2006; doi:10.1152/ajpheart.00142.2006
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Cytokines produced by bone marrow cells can contribute to functional improvement of the infarcted heart by protecting cardiomyocytes from ischemic injury

Masaya Takahashi, Tao-Sheng Li, Ryo Suzuki, Toshiro Kobayashi, Hiroshi Ito, Yasuhiro Ikeda, Masunori Matsuzaki, and Kimikazu Hamano

Department of Medical Bioregulation, Division of Cardiovascular Surgery and Medicine, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan

Submitted 7 February 2006 ; accepted in final form 17 March 2006

It is well known that the implantation of bone marrow mononuclear cells (BM-MNCs) into ischemic hearts can induce angiogenesis and improve cardiac function after myocardial infarction, but the precise mechanisms of these actions are unclear. We hypothesize that the cytokines produced by BM-MNCs play a key role in this cell-based therapy. BM-MNCs from rats were cultured under normoxic or hypoxic (1% O2) conditions for 24 h, and then supernatants were collected for study. ELISA and Western blotting analysis showed that various cytokines, including VEGF, IL-1beta, PDGF, and IGF-1, were produced from BM-MNCs, some of which were enhanced significantly under hypoxia stimulation. When compared with a control blank medium, the supernatants of BM-MNCs cultured under normoxic or hypoxic conditions inhibited apoptosis significantly and preserved the contractile capacity of isolated adult rat cardiomyocytes in vitro (P < 0.05). Using a rat model of acute myocardial infarction, we injected the supernatants of BM-MNCs or control medium intramyocardially on day 0 and then intraperitoneally on days 2, 4, and 6 after infarction. When compared with the control medium, the supernatants of BM-MNCs cultured under both normoxic or hypoxic conditions increased the microvessel density and decreased the fibrotic area in the infarcted myocardium significantly, contributing to remarkable improvement in cardiac function. Various cytokines were produced by BM-MNCs, and these cytokines contributed to functional improvement of the infarcted heart by directly preserving the contractile capacity of the myocardium, inhibiting apoptosis of cardiomyocytes, and inducing therapeutic angiogenesis of the infarcted heart.

ischemia; angiogenesis; bone marrow mononuclear cell; cytokine; apoptosis


Address for reprint requests and other correspondence: T.-S. Li, Dept. of Medical Bioregulation, Yamaguchi Univ. School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan (e-mail: litaoshe{at}yamaguchi-u.ac.jp)




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