TY - JOUR
T1 - Efficient transdifferentiation of human dermal fibroblasts into skeletal muscle
AU - Boularaoui, Selwa Mokhtar
AU - Abdel-Raouf, Khaled M.A.
AU - Alwahab, Noaf Salah Ali
AU - Kondash, Megan E.
AU - Truskey, George A.
AU - Teo, Jeremy Choon Meng
AU - Christoforou, Nicolas
N1 - Publisher Copyright:
Copyright © 2017 John Wiley & Sons, Ltd.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
KW - TGFβ/activin
KW - WNT
KW - collagen type I
KW - extracellular matrix
KW - receptor tyrosine kinase
KW - skeletal muscle
KW - transdifferentiation
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U2 - 10.1002/term.2415
DO - 10.1002/term.2415
M3 - Article
C2 - 28101909
AN - SCOPUS:85021352141
SN - 1932-6254
VL - 12
SP - e918-e936
JO - Journal of Tissue Engineering and Regenerative Medicine
JF - Journal of Tissue Engineering and Regenerative Medicine
IS - 2
ER -