2. Academic Validation
  3. Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors

Direct Reprogramming of Mouse Fibroblasts into Functional Skeletal Muscle Progenitors

  • Stem Cell Reports. 2018 May 8;10(5):1505-1521. doi: 10.1016/j.stemcr.2018.04.009.
Ori Bar-Nur 1,  Mattia F M Gerli 2,  Bruno Di Stefano 3,  Albert E Almada 4,  Amy Galvin 5,  Amy Coffey 3,  Aaron J Huebner 3,  Peter Feige 6,  Cassandra Verheul 3,  Priscilla Cheung 3,  Duygu Payzin-Dogru 3,  Sylvain Paisant 7,  Anthony Anselmo 8,  Ruslan I Sadreyev 8,  Harald C Ott 9,  Shahragim Tajbakhsh 7,  Michael A Rudnicki 6,  Amy J Wagers 4,  Konrad Hochedlinger 10
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Health Sciences and Technology, Institute of Human Movement Sciences and Sport, ETH Zurich, 8603 Schwerzenbach, Switzerland.
  • 2 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 3 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
  • 4 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 6 Sprott Centre for Stem Cell Research, Ottawa Health Research Institute, Ottawa, ON K1H 8L6, Canada.
  • 7 Stem Cells and Development Unit, Department of Developmental & Stem Cell Biology, Institut Pasteur, 75015 Paris, France; CNRS UMR 3738, Institut Pasteur, Paris, France.
  • 8 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 9 Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
  • 10 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: [email protected].
PMID: 29742392 DOI: 10.1016/j.stemcr.2018.04.009
Abstract

Skeletal muscle harbors quiescent stem cells termed satellite cells and proliferative progenitors termed myoblasts, which play pivotal roles during muscle regeneration. However, current technology does not allow permanent capture of these cell populations in vitro. Here, we show that ectopic expression of the myogenic transcription factor MyoD, combined with exposure to small molecules, reprograms mouse fibroblasts into expandable induced myogenic progenitor cells (iMPCs). iMPCs express key skeletal muscle stem and progenitor cell markers including Pax7 and Myf5 and give rise to dystrophin-expressing myofibers upon transplantation in vivo. Notably, a subset of transplanted iMPCs maintain Pax7 expression and sustain serial regenerative responses. Similar to satellite cells, iMPCs originate from Pax7+ cells and require Pax7 itself for maintenance. Finally, we show that myogenic progenitor cell lines can be established from muscle tissue following small-molecule exposure alone. This study thus reports on a robust approach to derive expandable myogenic stem/progenitor-like cells from multiple cell types.

Keywords

MyoD; Pax7; direct lineage reprogramming; induced muscle progenitor cells; muscular dystrophy; satellite cells; skeletal muscle; small molecules; transplantation.

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