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

Robert N. Judson, Marco Quarta, Menno J. Oudhoff, Hesham Soliman, Lin Yi, Chih Kai Chang, Gloria Loi, Ryan Vander Werff, Alissa Cait, Mark Hamer, Justin Blonigan, Patrick Paine, Linda T.N. Doan, Elena Groppa, Wen Jun He, Le Su, Regan H. Zhang, Peter Xu, Christine Eisner, Marcela LowIngrid Barta, Coral Ann B. Lewis, Colby Zaph, Mohammad M. Karimi, Thomas A. Rando, Fabio M. Rossi

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

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. Judson et al. show that lysine-methyltransferase Setd7 acts cytoplasmically to regulate the differentiation of skeletal muscle stem cells (MuSCs) by priming β-catenin for nuclear import. Pharmacological inhibition of Setd7 can provide a strategy to enhance the in vitro expansion and transplantation potential of murine and human MuSCs.

Original languageEnglish
Pages (from-to)177-190.e7
Number of pages21
JournalCell Stem Cell
Volume22
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

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

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