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Παρασκευή 26 Ιανουαρίου 2018

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

Publication date: Available online 25 January 2018
Source:Cell Stem Cell
Author(s): 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, WenJun He, Le Su, Regan H. Zhang, Peter Xu, Christine Eisner, Marcela Low, Ingrid Barta, Coral-Ann B. Lewis, Colby Zaph, Mohammad M. Karimi, Thomas A. Rando, Fabio M. Rossi
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.

Graphical abstract

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Teaser

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.


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