Blastocyst injection of wild type embryonic stem cells induces global corrections in mdx mice.
Duchenne muscular dystrophy (DMD) is an incurable neuromuscular degenerative disease, caused by a mutation in the dystrophin gene. Mdx mice recapitulate DMD features. Here we show that injection of wild-type (WT) embryonic stem cells (ESCs) into mdx blastocysts produces mice with improved pathology and function. A small fraction of WT ESCs incorporates into the mdx mouse nonuniformly to upregulate protein levels of dystrophin in the skeletal muscle. The chimeric muscle shows reduced regeneration and restores dystrobrevin, a dystrophin-related protein, in areas with high and with low dystrophin content. WT ESC injection increases the amount of fat in the chimeras to reach WT levels. ESC injection without dystrophin does not prevent the appearance of phenotypes in the skeletal muscle or in the fat. Thus, dystrophin supplied by the ESCs reverses disease in mdx mice globally in a dose-dependent manner.
Stillwell
Elizabeth
E
Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America.
Vitale
Joseph
J
Zhao
Qingshi
Q
Beck
Amanda
A
Schneider
Joel
J
Khadim
Farah
F
Elson
Genie
G
Altaf
Aneela
A
Yehia
Ghassan
G
Dong
Jia-hui
JH
Liu
Jing
J
Mark
Willie
W
Bhaumik
Mantu
M
Grange
Robert
R
Fraidenraich
Diego
D
D000818:Animals; D001755:Blastocyst; D002678:Chimera; D016189:Dystrophin / Q000235:genetics / Q000502:physiology; D049029:Dystrophin-Associated Proteins / Q000032:analysis; D004624:Embryo Transfer; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D008845:Microinjections; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000196:embryology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne; D012038:Regeneration
D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; C085339:apo-dystrophin 1; C098885:dystrobrevin