Notch2 negatively regulates myofibroblastic differentiation of myoblasts

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Abstract
Myofibroblasts are one of the key cellular components involved in fibrosis of skeletal muscle as well as in other tissues. Transforming growth factor‐β1 (TGF‐β1) 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‐β1‐induced non‐muscle fibrogenic tissue, we investigated whether Notch2 also has a distinctive role in myofibroblastic differentiation of myogenic cells induced by TGF‐β1. TGF‐β1 treatment of C2C12 myoblasts led to expression of myofibroblastic marker α‐smooth muscle actin (α‐SMA) and collagen I with concomitant downregulation of Notch2 expression. Overexpression of active Notch2 inhibited TGF‐β1‐induced expression of α‐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 α‐SMA and collagen I without TGF‐β1 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. J. Cell. Physiol. 210: 358–369, 2007.