Mononuclear Cells from Dedifferentiation of Mouse Myotubes Display Remarkable Regenerative Capability

Authors

  • Zhong Yang,

    1. College of Laboratory Medicine, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China
    2. Department of Anesthesia Perioperative and Pain Medicine, Boston, Massachusetts, USA
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  • Qiang Liu,

    1. Department of Anesthesia Perioperative and Pain Medicine, Boston, Massachusetts, USA
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  • Robert J. Mannix,

    1. Vascular Biology Program, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
    2. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA
    3. School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
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  • Xiaoyin Xu,

    1. Department of Radiology, Functional and Molecular Imaging Center, Brigham & Women's Hospital, Boston, Massachusetts, USA
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  • Hongli Li,

    1. Department of Anesthesia Perioperative and Pain Medicine, Boston, Massachusetts, USA
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  • Zhiyuan Ma,

    1. Department of Anesthesia Perioperative and Pain Medicine, Boston, Massachusetts, USA
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  • Donald E. Ingber,

    1. Vascular Biology Program, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
    2. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, Massachusetts, USA
    3. School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA
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  • Paul D. Allen,

    Corresponding author
    1. Department of Anesthesia Perioperative and Pain Medicine, Boston, Massachusetts, USA
    • Correspondence: Paul D. Allen, M.D., Ph.D., Department of Molecular Biosciences, University of California at Davis, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, Davis, California 95616, USA. Telephone: 530-752-5022; e-mail: pdallen@ucdavis.edu

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  • Yaming Wang

    1. Department of Anesthesia Perioperative and Pain Medicine, Boston, Massachusetts, USA
    2. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
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Abstract

Certain lower organisms achieve organ regeneration by reverting differentiated cells into tissue-specific progenitors that re-enter embryonic programs. During muscle regeneration in the urodele amphibian, postmitotic multinucleated skeletal myofibers transform into mononucleated proliferating cells upon injury, and a transcription factor-msx1 plays a role in their reprograming. Whether this powerful regeneration strategy can be leveraged in mammals remains unknown, as it has not been demonstrated that the dedifferentiated progenitor cells arising from muscle cells overexpressing Msx1 are lineage-specific and possess the same potent regenerative capability as their amphibian counterparts. Here, we show that ectopic expression of Msx1 reprograms postmitotic, multinucleated, primary mouse myotubes to become proliferating mononuclear cells. These dedifferentiated cells reactivate genes expressed by embryonic muscle progenitor cells and generate only muscle tissue in vivo both in an ectopic location and inside existing muscle. More importantly, distinct from adult muscle satellite cells, these cells appear both to fuse with existing fibers and to regenerate myofibers in a robust and time-dependent manner. Upon transplantation into a degenerating muscle, these dedifferentiated cells generated a large number of myofibers that increased over time and replenished almost half of the cross-sectional area of the muscle in only 12 weeks. Our study demonstrates that mammals can harness a muscle regeneration strategy used by lower organisms when the same molecular pathway is activated. Stem Cells 2014;32:2492–2501