title: Efficient transdifferentiation of human dermal fibroblasts into skeletal muscle.
abstract: Skeletal muscle holds significant regenerative potential but is incapable of restoring tissue loss caused by severe injury, congenital defects or tumour ablation. Consequently, skeletal muscle models are being developed to study human pathophysiology and regeneration. Their physiological accuracy, however, is hampered by the lack of an easily accessible human cell source that is readily expandable and capable of efficient differentiation. MYOD1, a master gene regulator, induces transdifferentiation of a variety of cell types into skeletal muscle, although inefficiently in human cells. Here we used MYOD1 to establish its capacity to induce skeletal muscle transdifferentiation of human dermal fibroblasts under baseline conditions. We found significant transdifferentiation improvement via transforming growth factor-β/activin signalling inhibition, canonical WNT signalling activation, receptor tyrosine kinase binding and collagen type I utilization. Mechanistically, manipulation of individual signalling pathways modulated the transdifferentiation process via myoblast proliferation, lowering the transdifferentiation threshold and inducing cell fusion. Overall, we used transdifferentiation to achieve the robust derivation of human skeletal myotubes and have described the signalling pathways and mechanisms regulating this process. Copyright © 2017 John Wiley & Sons, Ltd.
authors.affiliation: Department of Biomedical Engineering, Khalifa University, Abu Dhabi, UAE.
authors.forename: Selwa Mokhtar
authors.initials: SM
authors.lastname: Boularaoui
authors.affiliation: Department of Biomedical Engineering, Khalifa University, Abu Dhabi, UAE.
authors.forename: Khaled M A
authors.initials: KMA
authors.lastname: Abdel-Raouf
authors.affiliation: School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Noaf Salah Ali
authors.initials: NSA
authors.lastname: Alwahab
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Kondash
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Truskey
authors.affiliation: Department of Biomedical Engineering, Khalifa University, Abu Dhabi, UAE.
authors.forename: Jeremy Choon Meng
authors.initials: JCM
authors.lastname: Teo
authors.affiliation: Department of Biomedical Engineering, Khalifa University, Abu Dhabi, UAE.|Department of Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Nicolas
authors.identifier: 0000-0003-4594-6919
authors.initials: N
authors.lastname: Christoforou
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002459:Cell Fusion; D002460:Cell Line; D054338:Cell Transdifferentiation; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D020405:Dermis / Q000166:cytology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology*; D017570:MyoD Protein / Q000378:metabolism*; D061848:Optical Imaging; D010641:Phenotype; D015398:Signal Transduction
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D002118:Calcium
keywords: TGFβ/activin; WNT; collagen type I; extracellular matrix; receptor tyrosine kinase; skeletal muscle; transdifferentiation