Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential§

Authors

  • Yang Liu,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
    2. Children's Hospital, Chongqing Medical University, Chongqing, People's Republic of China
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    • Contributed equally as first authors.

  • Xiaohua Jiang,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
    2. Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University-the Chinese University of Hong Kong, Guangzhou, People's Republic of China
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    • Contributed equally as first authors.

  • Xiaohu Zhang,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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    • Contributed equally as first authors.

  • Rui Chen,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Tingting Sun,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Kin Lam Fok,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Jianda Dong,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Lai Ling Tsang,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Shaoqiong Yi,

    1. Department of Applied Molecular Biology, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, People's Republic of China
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  • Yechun Ruan,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Jinghui Guo,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Mei Kuen Yu,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Yuemin Tian,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Yiu Wa Chung,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Mo Yang,

    1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
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  • Wenming Xu,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
    2. Sichuan University–the Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Women's and Children's Hospital, Sichuan University, Chengdu, People's Republic of China
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  • Chin Man Chung,

    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
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  • Tingyu Li,

    Corresponding author
    1. Children's Hospital, Chongqing Medical University, Chongqing, People's Republic of China
    • Children's Hospital, Chongqing Medical University, Chongqing, China
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    • Telephone: 8623-63628660; Fax: 8623-63626904

    • Contributed equally as corresponding authors.

  • Hsiao Chang Chan

    Corresponding author
    1. Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Shatin, Hong Kong
    2. Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University-the Chinese University of Hong Kong, Guangzhou, People's Republic of China
    • Epithelial Cell Biology Research Center, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, Hong Kong
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    • Telephone: 852-26961105; Fax: 852-26037155

    • Contributed equally as corresponding authors.


  • Author contributions: Y.L. and X.Z.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; X.J.: design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; R.C., T.S., K.L.F., J.D., L.L.T., S.Y., Y.R., J.G., M.K.Y., Y.T., and W.X.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; Y.W.C.: collection and/or assembly of data, data analysis and interpretation, administrative support, and final approval of manuscript; M.Y.: data analysis and interpretation, provision of study material, and final approval of manuscript; C.M.C.: collection and/or assembly of data and data analysis and interpretation, T.L.: conception and design, financial support, provision of study material, data analysis and interpretation, and final approval of manuscript; H.C.C: conception and design, financial support, provision of study material, data analysis and interpretation, manuscript writing, and final approval of manuscript.

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

  • §

    First published online in STEM CELLSEXPRESS November 3, 2011.

Abstract

Stem cell transplantation has been shown to improve functional outcome in degenerative and ischemic disorders. However, low in vivo survival and differentiation potential of the transplanted cells limits their overall effectiveness and thus clinical usage. Here we show that, after in vitro induction of neuronal differentiation and dedifferentiation, on withdrawal of extrinsic factors, mesenchymal stem cells (MSCs) derived from bone marrow, which have already committed to neuronal lineage, revert to a primitive cell population (dedifferentiated MSCs) retaining stem cell characteristics but exhibiting a reprogrammed phenotype distinct from their original counterparts. Of therapeutic interest, the dedifferentiated MSCs exhibited enhanced cell survival and higher efficacy in neuronal differentiation compared to unmanipulated MSCs both in vitro and in vivo, with significantly improved cognition function in a neonatal hypoxic–ischemic brain damage rat model. Increased expression of bcl-2 family proteins and microRNA-34a appears to be the important mechanism giving rise to this previously undefined stem cell population that may provide a novel treatment strategy with improved therapeutic efficacy. STEM CELLS 2011;29:2077–2089.

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