Regulation of Differentiation Potential of Human Mesenchymal Stem Cells by Intracytoplasmic Delivery of Coactivator-Associated Arginine Methyltransferase 1 Protein Using Cell-Penetrating Peptide§

Authors

  • Junghyun Jo,

    1. Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea
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  • Haengseok Song,

    1. Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea
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  • Sang Gyu Park,

    1. Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea
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  • Soo-Hong Lee,

    1. Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea
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  • Jung-Jae Ko,

    1. Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea
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  • Jong-Hyuk Park,

    1. Division of Development and Physiology, School of Biological Sciences and Chemistry, Institute for Basic Sciences, College of Natural Science, Sungshin Women's University, Seoul, Korea
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  • Jaemin Jeong,

    1. Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Science, Seoul, Korea
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  • Yong-Pil Cheon,

    Corresponding author
    1. Division of Development and Physiology, School of Biological Sciences and Chemistry, Institute for Basic Sciences, College of Natural Science, Sungshin Women's University, Seoul, Korea
    • Division of Development and Physiology, School of Biological Sciences and Chemistry, Institute for Basic Sciences, Sungshin Women's University, Seoul 136-742, Korea
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    • Telephone: 82-2-920-7639; Fax: 82-2-920-2093

  • Dong Ryul Lee

    Corresponding author
    1. Department of Biomedical Science, College of Life Science, CHA University, Seoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
    • Department of Biomedical Science, College of Life Science, CHA University, 606-5 Yeoksam-dong, Gangnam-gu, Seoul 135-081 Korea
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    • Telephone: 82-2-3468-3421; Fax: 82-2-3468-3466


  • Author contributions: J.Jo and H.S.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; S.G.P.: collection and/or assembly of data and data analysis and interpretation; S.H.L.: provision of study material or patients and data analysis and interpretation; J.J.K.: financial support, administrative support, and collection and/or assembly of data; J.H.P.: conception and design, collection and/or assembly of data, and data analysis and interpretation; J. Jeong: collection and/or assembly of data and data analysis and interpretation; Y.P.C.: conception and design, provision of study material or patients, collection and/or assembly of data, and final approval of manuscript; D.R.L.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript. J.J. and H.S. contributed equally to this article.

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

  • §

    First published online in STEM CELLSEXPRESS June 13, 2012.

Abstract

Recent studies suggest that epigenetic modifications, such as DNA methylation and histone modification, can alter the differentiation potential of stem cells or progenitor cells. Specifically, coactivator-associated arginine methyltransferase 1 (CARM1) is known to act as a coactivator for various transcription factors and to regulate gene expression by chromatin remodeling through histone methylation. Here, for the first time, we have used direct protein delivery of CARM1 using cell-penetrating peptide (CPP) to regulate the differentiation potential of human mesenchymal stem cells (hMSCs). Immunofluorescence showed that the CPP-CARM1 protein is successfully delivered into the nuclei of hMSCs. Further experiments using immunofluorescence and Western blotting showed that the delivered CARM1 protein can effectively methylate the arginine 17 residue of histone H3 in both bone marrow (BM)- and adipose-derived (AD)-hMSCs, thus suggesting that the CARM1 protein delivered by the CPP system is biologically active in hMSCs. Chromatin immunoprecipitation (ChIP) assay and genome-wide gene expression profiling supported the result that delivered CARM1 protein can cause chromatin remodeling through histone methylation. Finally, the CPP-CARM1 protein efficiently elevated the differentiation efficiency of BM-hMSCs and AD-hMSCs into adipogenic, osteogenic, and myogenic cell lineages in vitro. Altered expression of critical genes after hMSC differentiation was reconfirmed by real-time reverse transcription polymerase chain reaction (qRT-PCR). Collectively, our results suggest that CPP-CARM1 can elevate the differentiation potential of hMSCs into various cell types, and that this system using CPP is a useful tool for exogenous protein delivery in clinical applications of cell-based therapy. Stem Cells2012;30:1703–1713

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