title: Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras.
abstract: Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin-negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle. Inflammation, regeneration and fibrosis are observed at the whole organ level, both in dystrophin-negative and dystrophin-positive portions of the chimeric tissues. Skeletal and cardiac muscle function are also decreased to mdx levels. In contrast to mdx heterozygous carriers, which show no significant phenotypes, these effects are even observed in chimeras with low levels of mdx ESC incorporation (10%-30%). Chimeric mice lack typical compensatory utrophin upregulation, and show pathological remodeling of Connexin-43. In addition, dystrophin-negative and dystrophin-positive isolated cardiomyocytes show augmented calcium response to mechanical stress, similar to mdx cells. These global effects highlight a novel role of mdx ESCs in triggering muscular dystrophy even when only low amounts are present. Stem Cells 2017;35:597-610.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.
authors.forename: J Patrick
authors.initials: JP
authors.lastname: Gonzalez
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Newark, New Jersey, USA.
authors.forename: Sergii
authors.initials: S
authors.lastname: Kyrychenko
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Newark, New Jersey, USA.
authors.forename: Viktoriia
authors.initials: V
authors.lastname: Kyrychenko
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schneider
authors.affiliation: Department of Pediatrics, Rutgers Biomedical and Health Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Celine J
authors.initials: CJ
authors.lastname: Granier
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Himelman
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Lahey
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.
authors.forename: Qingshi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Genome Editing Core Facility, Office of Research Advancement, New Brunswick, New Jersey, USA.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Yehia
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.|Department of Pharmacology, Physiology and Neuroscience, Newark, New Jersey, USA.|Department of Anesthesiology, Rutgers Biomedical and Health Sciences, New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.affiliation: Department of Pediatrics, Rutgers Biomedical and Health Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Mantu
authors.initials: M
authors.lastname: Bhaumik
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, Newark, New Jersey, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Shirokova
authors.affiliation: Department of Cell Biology and Molecular Medicine, Newark, New Jersey, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Fraidenraich
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002678:Chimera / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D016189:Dystrophin / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D006334:Heart Function Tests; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000473:pathology*; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D012038:Regeneration
chemical_list: D018031:Connexin 43; D016189:Dystrophin; D002118:Calcium
keywords: Cardiomyopathy; Chimeras; Connexin-43; Dystrophin; Embryonic stem cells; Muscular dystrophy; Utrophin