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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Animals
  • Cell Differentiation / drug effects
  • Cell Line
  • Cell Lineage / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Cell Self Renewal / drug effects
  • Cells, Cultured
  • Gene Deletion
  • Mice
  • Muscle Development*
  • Muscle, Skeletal / physiology
  • MyoD Protein / metabolism
  • Protein Binding / drug effects
  • Protein Methyltransferases / antagonists & inhibitors*
  • Protein Methyltransferases / metabolism
  • Pyrrolidines / pharmacology
  • Regeneration / drug effects
  • Stem Cell Transplantation*
  • Stem Cells / cytology*
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Sulfonamides / pharmacology
  • Tetrahydroisoquinolines / pharmacology
  • beta Catenin / metabolism

Substances

  • (R)-PFI-2
  • MyoD Protein
  • Pyrrolidines
  • Sulfonamides
  • Tetrahydroisoquinolines
  • beta Catenin
  • Protein Methyltransferases
  • Setd7 protein, mouse