Activation of Notch Signaling During Ex Vivo Expansion Maintains Donor Muscle Cell Engraftment§

Authors

  • Maura H. Parker,

    Corresponding author
    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, District of Columbia, USA
    • Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Mail Stop D1-100, P.O. Box 19024, Seattle, Washington 98109-1024, USA

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    • Telephone: 206-667-1623; Fax: 206-667-6124;

  • Carol Loretz,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, District of Columbia, USA
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  • Ashlee E. Tyler,

    1. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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  • William J. Duddy,

    1. Center for Genetic Medicine, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
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  • John K. Hall,

    1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado, USA
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  • Bradley B. Olwin,

    1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado, USA
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  • Irwin D. Bernstein,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, District of Columbia, USA
    2. Department of Pediatrics, University of Washington, Seattle, Washington, District of Columbia, USA
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  • Rainer Storb,

    1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, District of Columbia, USA
    2. Department of Medicine, University of Washington, Seattle, Washington, District of Columbia, USA
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  • Stephen J. Tapscott

    1. Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
    2. Department of Neurology, University of Washington, Seattle, Washington, USA
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  • Authors Contributions: M.P.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing; C.L. and A.E.T.: collection and/or assembly of data; W.J.D., J.K.H., B.B.O., I.D.B.: provision of study material; R.S.: conception and design and data analysis and interpretation; S.J.T.: conception and design, data analysis and interpretation, manuscript writing, and financial support.

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

  • §

    First published online in STEM CELLSEXPRESS August 3, 2012.

Abstract

Transplantation of myogenic stem cells possesses great potential for long-term repair of dystrophic muscle. However, a single donor muscle biopsy is unlikely to provide enough cells to effectively transplant the muscle mass of a patient affected by muscular dystrophy. Expansion of cells ex vivo using traditional culture techniques significantly reduces engraftment potential. We hypothesized that activation of Notch signaling during ex vivo expansion would maintain donor cell engraftment potential. In this study, we expanded freshly isolated canine muscle-derived cells on tissue culture plates coated with Delta-1ext-IgG to activate Notch signaling or with human IgG as a control. A model of canine-to-murine xenotransplantation was used to quantitatively compare canine muscle cell engraftment and determine whether engrafted donor cells could function as satellite cells in vivo. We show that Delta-1ext-IgG inhibited differentiation of canine muscle-derived cells and increased the level of genes normally expressed in myogenic precursors. Moreover, cells expanded on Delta-1ext-IgG resulted in a significant increase in the number of donor-derived fibers, as compared to cells expanded on human IgG, reaching engraftment levels similar to freshly isolated cells. Importantly, cells expanded on Delta-1ext-IgG engrafted to the recipient satellite cell niche and contributed to further regeneration. A similar strategy of expanding human muscle-derived cells on Notch ligand might facilitate engraftment and muscle regeneration for patients affected with muscular dystrophy. STEM Cells2012;30:2212–2220

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