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Cell Stem Cell. 2018 Feb 1;22(2):177-190.e7. doi: 10.1016/j.stem.2017.12.010. Epub 2018 Jan 25.

Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential.

Author information

1
Biomedical Research Centre, Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada; STEMCELL Technologies Inc., Vancouver, BC, Canada.
2
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, CA, USA; Center for Tissue Regeneration, Repair and Restoration, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
3
Biomedical Research Centre, Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada; Center of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
4
Biomedical Research Centre, Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada.
5
Biomedical Research Centre, Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada; HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
6
Biomedical Research Centre, Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada; Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.
7
MRC London Institute of Medical Sciences, Imperial College, London, UK.
8
Biomedical Research Centre, Department of Medical Genetics, 2222 Health Sciences Mall, University of British Columbia, Vancouver, BC, Canada. Electronic address: fabio@brc.ubc.ca.

Abstract

The development of cell therapy for repairing damaged or diseased skeletal muscle has been hindered by the inability to significantly expand immature, transplantable myogenic stem cells (MuSCs) in culture. To overcome this limitation, a deeper understanding of the mechanisms regulating the transition between activated, proliferating MuSCs and differentiation-primed, poorly engrafting progenitors is needed. Here, we show that methyltransferase Setd7 facilitates such transition by regulating the nuclear accumulation of β-catenin in proliferating MuSCs. Genetic or pharmacological inhibition of Setd7 promotes in vitro expansion of MuSCs and increases the yield of primary myogenic cell cultures. Upon transplantation, both mouse and human MuSCs expanded with a Setd7 small-molecule inhibitor are better able to repopulate the satellite cell niche, and treated mouse MuSCs show enhanced therapeutic potential in preclinical models of muscular dystrophy. Thus, Setd7 inhibition may help bypass a key obstacle in the translation of cell therapy for muscle disease.

KEYWORDS:

SET domain; WNT; differentiation; methylation; methyltransferase; muscle stem cells; myogenesis; satellite cells; skeletal muscle; β-catenin

PMID:
29395054
PMCID:
PMC6031334
DOI:
10.1016/j.stem.2017.12.010
[Indexed for MEDLINE]
Free PMC Article

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