Pretreatment of rat bone marrow mesenchymal stem cells with a combination of hypergravity and 5-azacytidine enhances therapeutic efficacy for myocardial infarction

Authors

  • Shu-Kuan Ling,

    1. Dept. of Life Science and Engineering, Harbin Institute of Technology, Harbin 150001, China
    2. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Rui Wang,

    1. Dept. of Stomatology, the 306th Hospital of PLA, Beijing 100101, China
    2. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Zhong-Quan Dai,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Jie-Lin Nie,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Hong-Hui Wang,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Ying-Jun Tan,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Hong-Qing Cao,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Zeng-Ming Huang,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Yu-Min Wan,

    1. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
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  • Ying-Hui Li

    Corresponding author
    1. Dept. of Life Science and Engineering, Harbin Institute of Technology, Harbin 150001, China
    2. State Key Laboratory of Space Medicine Fundamentals and Application, Astronaut Research and Training Center of China, Beijing 100094, China
    • Dept. of Life Science and Engineering, Harbin Institute of Technology, Harbin 150001, China
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Abstract

Background and Purpose: The in vivo cardiac differentiation and functional effects of unmodified adult bone marrow mesenchymal stem cells (BMSCs) after myocardial infarction (MI) is controversial. Our previous results suggested that hypergravity promoted the cardiomyogenic differentiation of BMSCs, and thus we postulated that ex vivo pretreatment of BMSCs using hypergravity and 5-azacytidine (5-Aza) would lead to cardiomyogenic differentiation and result in superior biological and functional effects on cardiac regeneration of infarcted myocardium. Methods: We used a rat MI model generated by ligation of the coronary artery. Homogeneous rat BMSCs were isolated, culture expanded, and differentiated into a cardiac lineage by adding hypergravity (2G) for 3 days and 5-Aza (50 lmol/L, 24 h). Rats underwent BMSCs (labeled with DAPI) injection after the infarction and were randomized into five groups. Group A rats received the control medium, Group B rats received unmodified BMSCs, Group C rats received BMSCs treated with hypergravity, Group D rats received BMSCs treated with 5-Aza, and Group E rats received BMSCs treated with 5-Aza and hypergravity (n = 6). Results: After hypergravity and 5-Aza treatment, BMSCs showed positive for the early muscle and cardiac markers GATA-4, MEF-2, and Nkx2-5 with RT-PCR. We also found that hypergravity could enhance the activities of MEF-2 via promoting the nuclear export of HDAC5. The frozen section showed that the implanted BMSCs labeled with DAPI survived and angiogenesis was identified at the implantation site. In Groups B, C, D, and E rats, pre-treated BMSCs colocalized with α-actinin, and Group E rats showed a significantly larger increase in left ventricular function. Conclusions: The biological ex vivo cardiomyogenic differentiation of adult BMSCs with hypergravity and 5-Aza prior to their transplantation is feasible and appears to improve their in vivo cardiac differentiation as well as the functional recovery in a rat model of the infarcted myocardium. © 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2011

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