Impact of Myocardial Infarct Proteins and Oscillating Pressure on the Differentiation of Mesenchymal Stem Cells: Effect of Acute Myocardial Infarction on Stem Cell Differentiation

Authors

  • Sung-A Chang,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
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  • Eun Ju Lee,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
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  • Hyun-Jae Kang M.D., Ph.D.,

    Corresponding author
    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
    3. Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
    • National Research Laboratory for Cardiovascular Stem Cells, Department of Internal Medicine, Seoul National University College of Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea. Telephone: 82-2-2072-2226; Fax: 82-2-766-8904
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  • Shu-Ying Zhang,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Ji-Hyun Kim,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Lian Li,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Seock-Won Youn,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Choon-Soo Lee,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Keum-Hyun Kim,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Joo-Yun Won,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
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  • Jong-Woo Sohn,

    1. National Research Laboratory for Cell Physiology, Department of Physiology, Seoul National University College of Medicine, Seoul, Korea
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  • Kyung-Woo Park,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
    3. Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
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  • Hyun-Jai Cho,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
    3. Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
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  • Sung-Eun Yang,

    1. Medipost Inc., Seoul, Korea
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  • Won Il Oh,

    1. Medipost Inc., Seoul, Korea
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  • Yoon Sun Yang,

    1. Medipost Inc., Seoul, Korea
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  • Won-Kyung Ho,

    1. National Research Laboratory for Cell Physiology, Department of Physiology, Seoul National University College of Medicine, Seoul, Korea
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  • Young-Bae Park,

    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
    3. Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
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  • Hyo-Soo Kim M.D., Ph.D.

    Corresponding author
    1. National Research Laboratory for Cardiovascular Stem Cells, Seoul, Korea
    2. Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
    3. Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea
    • National Research Laboratory for Cardiovascular Stem Cells, Department of Internal Medicine, Seoul National University College of Medicine, Innovative Research Institute for Cell Therapy, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Republic of Korea. Telephone: 82-2-2072-2226; Fax: 82-2-766-8904;
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Abstract

Stem cell transplantation in acute myocardial infarction (AMI) has emerged as a promising therapeutic option. We evaluated the impact of AMI on mesenchymal stem cell (MSC) differentiation into cardiomyocyte lineage. Cord blood-derived human MSCs were exposed to in vitro conditions simulating in vivo environments of the beating heart with acute ischemia, as follows: (a) myocardial proteins or serum obtained from sham-operated rats, and (b) myocardial proteins or serum from AMI rats, with or without application of oscillating pressure. Expression of cardiac-specific markers on MSCs was greatly induced by the infarcted myocardial proteins, compared with the normal proteins. It was also induced by application of oscillating pressure to MSCs. Treatment of MSCs with infarcted myocardial proteins and oscillating pressure greatly augmented expression of cardiac-specific genes. Such expression was blocked by inhibitor of transforming growth factor β1 (TGF-β1) or bone morphogenetic protein-2 (BMP-2). In vitro cellular and electrophysiologic experiments showed that these differentiated MSCs expressing cardiomyocyte-specific markers were able to make a coupling with cardiomyocytes but not to selfbeat. The pathophysiologic significance of in vitro results was confirmed using the rat AMI model. The protein amount of TGF-β1 and BMP-2 in myocardium of AMI was significantly higher than that in normal myocardium. When MSCs were transplanted to the heart and analyzed 8 weeks later, they expressed cardiomyocyte-specific markers, leading to improved cardiac function. These in vitro and in vivo results suggest that infarct-related biological and physical factors in AMI induce commitment of MSCs to cardiomyocyte-like cells through TGF-β/BMP-2 pathways.

Disclosure of potential conflicts of interest is found at the end of this article.

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