title: A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles.
abstract: : Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies.
  
  
  
  This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development.
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia uli.schmidt@geneabiocells.com.
authors.forename: Leslie
authors.initials: L
authors.lastname: Caron
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia.
authors.forename: Devaki
authors.initials: D
authors.lastname: Kher
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Kian Leong
authors.initials: KL
authors.lastname: Lee
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia.
authors.forename: Robert
authors.initials: R
authors.lastname: McKernan
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia.
authors.forename: Biljana
authors.initials: B
authors.lastname: Dumevska
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Hidalgo
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Main
authors.affiliation: Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy Vita-Salute San Raffaele University, Milano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ferri
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Petek
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Miller
authors.affiliation: Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Gabellini
authors.affiliation: Genea Biocells Pty. Ltd., Sydney, New South Wales, Australia Genea Biocells US Inc., San Diego, California, USA.
authors.forename: Uli
authors.initials: U
authors.lastname: Schmidt
mesh_terms: D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D006801:Humans; D018482:Muscle, Skeletal / Q000166:cytology*; D020391:Muscular Dystrophy, Facioscapulohumeral; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000166:cytology*; D016133:Polymerase Chain Reaction
keywords: Embryonic stem cells; Induced pluripotent stem cells; Muscular dystrophy; Pluripotent stem cells; Skeletal muscle