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Intrinsic cell memory reinforces myogenic commitment of pericyte-derived iPSCs

Authors

  • Mattia Quattrocelli,

    1. Translational Cardiomyology, Stem Cell Institute, Katholieke Universiteit Leuven, Belgium
    2. Department of Experimental Medicine and Biochemical Sciences, Section of Biochemistry and Molecular Biology, University of Perugia, Italy
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    • These authors contributed equally to this work.

  • Giacomo Palazzolo,

    1. Translational Cardiomyology, Stem Cell Institute, Katholieke Universiteit Leuven, Belgium
    2. Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy
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    • These authors contributed equally to this work.

  • Giuseppe Floris,

    1. Department of General Medical Oncology, Laboratory of Experimental Oncology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium
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  • Patrick Schöffski,

    1. Department of General Medical Oncology, Laboratory of Experimental Oncology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Belgium
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  • Luigi Anastasia,

    1. Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Milan, Italy
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  • Aldo Orlacchio,

    1. Department of Experimental Medicine and Biochemical Sciences, Section of Biochemistry and Molecular Biology, University of Perugia, Italy
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  • Thierry Vandendriessche,

    1. Flanders Institute for Biotechnology (VIB), Vesalius Research Center, Katholieke Universiteit Leuven, Belgium
    2. Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Belgium
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  • Marinee KL Chuah,

    1. Flanders Institute for Biotechnology (VIB), Vesalius Research Center, Katholieke Universiteit Leuven, Belgium
    2. Faculty of Medicine and Pharmacy, Free University of Brussels (VUB), Belgium
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  • Giulio Cossu,

    1. Division of Regenerative Medicine, San Raffaele Scientific Institute, Milan, Italy
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  • Catherine Verfaillie,

    1. Stem Cell Institute, Katholieke Universiteit Leuven, Belgium
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  • Maurilio Sampaolesi

    Corresponding author
    1. Translational Cardiomyology, Stem Cell Institute, Katholieke Universiteit Leuven, Belgium
    2. Human Anatomy, C.I.T, University of Pavia, Italy
    • Stem Cell Research Institute, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium.
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  • No conflicts of interest were declared.

Abstract

Mesoangioblasts (MABs) are a subset of muscle-derived pericytes able to restore dystrophic phenotype in mice and dogs. However, their lifespan is limited and they undergo senescence after 25–30 population doublings. Recently, induced pluripotent stem cells (iPSCs) generated from reprogrammed fibroblasts have been demonstrated to have in vitro and in vivo myogenic potential when sorted for the SM/C-2.6 antigen. Furthermore, chimeric mice from mdx-iPSCs (DYS-HAC) cells showed tissue-specific expression of dystrophin. Nevertheless, myogenic differentiation protocols and the potential of iPSCs generated from different cell sources still present unanswered questions. Here we show that iPSCs generated from prospectively sorted MABs (MAB-iPSCs) are pluripotent as fibroblast-derived iPSCs (f-iPSCs). However, both teratoma formation and genetic cell manipulation assays identify a durable epigenetic memory in MAB-iPSCs, resulting in stronger myogenic commitment. Striated muscle tissue accounts for up to 70% of MAB-iPSC teratomas. Moreover, transfection with Pax3 and Pax7 induces a more robust myogenic differentiation in MAB-iPSCs than in f-iPSCs. A larger amount of CD56+ progenitors can be sorted from the MAB-iPSCs differentiating pool and, after transplantation into αsg-KO mice, can efficiently participate to skeletal muscle regeneration and restore αsg expression. Our data strongly suggest that iPSCs are a heterogeneous population and, when generated from myogenic adult stem cells, they exhibit a stronger commitment, paving the way for creating custom-made cell protocols for muscular dystrophies. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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