1. Inhibition of Methyltransferase Setd7 Allows the In Vitro Expansion of Myogenic Stem Cells with Improved Therapeutic Potential.
- Author
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Judson RN, Quarta M, Oudhoff MJ, Soliman H, Yi L, Chang CK, Loi G, Vander Werff R, Cait A, Hamer M, Blonigan J, Paine P, Doan LTN, Groppa E, He W, Su L, Zhang RH, Xu P, Eisner C, Low M, Barta I, Lewis CB, Zaph C, Karimi MM, Rando TA, and Rossi FM
- Subjects
- 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, Histone-Lysine N-Methyltransferase, Mice, Muscle, Skeletal physiology, MyoD Protein metabolism, Protein Binding drug effects, Protein Methyltransferases metabolism, Pyrrolidines pharmacology, Regeneration drug effects, Stem Cells drug effects, Stem Cells metabolism, Sulfonamides pharmacology, Tetrahydroisoquinolines pharmacology, beta Catenin metabolism, Muscle Development, Protein Methyltransferases antagonists & inhibitors, Stem Cell Transplantation, Stem Cells cytology
- 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2018
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