Notch2 negatively regulates myofibroblastic differentiation of myoblasts.
Myofibroblasts are one of the key cellular components involved in fibrosis of skeletal muscle as well as in other tissues. Transforming growth factor-beta1 (TGF-beta1) stimulates differentiation of mesenchymal cells into myofibroblasts, but little is known about the regulatory mechanisms of myofibroblastic differentiation. Since Notch2 was shown to be downregulated in TGF-beta1-induced non-muscle fibrogenic tissue, we investigated whether Notch2 also has a distinctive role in myofibroblastic differentiation of myogenic cells induced by TGF-beta1. TGF-beta1 treatment of C2C12 myoblasts led to expression of myofibroblastic marker alpha-smooth muscle actin (alpha-SMA) and collagen I with concomitant downregulation of Notch2 expression. Overexpression of active Notch2 inhibited TGF-beta1-induced expression of alpha-SMA and collagen I. Interestingly, transient knockdown of Notch2 by siRNA in C2C12 myoblasts and primary cultured muscle-derived progenitor cells resulted in differentiation into myofibroblastic cells expressing alpha-SMA and collagen I without TGF-beta1 treatment. Furthermore, we found Notch3 was counter-regulated by Notch2 in C2C12 cells. These findings suggest that Notch2 is inhibiting differentiation of myoblasts into myofibroblasts with downregulation of Notch3 expression.
Ono
Yusuke
Y
Department of Medicine and Science in Sports and Exercise, Tohoku University Graduate School of Medicine, Sendai, Japan.
Sensui
Hiroomi
H
Okutsu
Saeko
S
Nagatomi
Ryoichi
R
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D024042:Collagen Type I / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051883:Receptor, Notch2 / Q000378:metabolism*; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects / Q000235:genetics
D000199:Actins; D024042:Collagen Type I; D034741:RNA, Small Interfering; D051883:Receptor, Notch2; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D053773:Transforming Growth Factor beta1; C499373:Notch3 protein, mouse; C498862:Acta2 protein, rat