CRISPR/Cas9 editing of directly reprogrammed myogenic progenitors restores dystrophin expression in a mouse model of muscular dystrophy.

Autor:	Domenig SA; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland., Bundschuh N; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland., Lenardič A; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland., Ghosh A; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland; Functional Genomics Center Zurich, Swiss Federal Institute of Technology (ETH) Zurich and University of Zurich, Zurich, Switzerland., Kim I; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland., Qabrati X; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland., D'Hulst G; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland., Bar-Nur O; Laboratory of Regenerative and Movement Biology, Institute of Human Movement Sciences and Sport, Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland. Electronic address: Ori.bar-nur@hest.ethz.ch.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2022 Feb 08; Vol. 17 (2), pp. 321-336. Date of Electronic Publication: 2022 Jan 06.
DOI:	10.1016/j.stemcr.2021.12.003
Abstrakt:	Genetic mutations in dystrophin manifest in Duchenne muscular dystrophy (DMD), the most commonly inherited muscle disease. Here, we report on reprogramming of fibroblasts from two DMD mouse models into induced myogenic progenitor cells (iMPCs) by MyoD overexpression in concert with small molecule treatment. DMD iMPCs proliferate extensively, while expressing myogenic stem cell markers including Pax7 and Myf5. Additionally, DMD iMPCs readily give rise to multinucleated myofibers that express mature skeletal muscle markers; however, they lack DYSTROPHIN expression. Utilizing an exon skipping-based approach with CRISPR/Cas9, we report on genetic correction of the dystrophin mutation in DMD iMPCs and restoration of protein expression in vitro. Furthermore, engraftment of corrected DMD iMPCs into the muscles of dystrophic mice restored DYSTROPHIN expression and contributed to the muscle stem cell reservoir. Collectively, our findings report on a novel in vitro cellular model for DMD and utilize it in conjunction with gene editing to restore DYSTROPHIN expression in vivo. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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