Abstract
Purpose :
In primary lens cell cultures, inhibitors of either ErbBs (EGF receptor family members) or ERK kinases prevent TGFβ from inducing epithelial-to-myofibroblast transition (EMyT). Despite its relevance for fibrotic PCO, we do not understand why ErbB activity is essential for TGFβ-induced EMyT of lens cells.
Methods :
Western blotting and immunofluorescent microscopy were used to assess the expression of markers of lens cell differentiation in serum-free primary cultures of embryonic chick lens epithelial cells grown on laminin (DCDMLs). Activation of ErbBs, Smad3, ERK, and p38 was assessed using phospho-specific antibodies.
Results :
Inhibitors of either ERK or ErbB signaling block TGFΒ from upregulating both early (fibronectin) and late (αSMA) markers of myofibroblast differentiation. TGFβ stimulates ERK in DCDMLs within 1.5 h. Kinase inhibitors of ErbBs, but not of other growth factor receptors active in lens cells, reduce the phosphoERK signal to below basal levels in either the absence or presence of TGFβ. This effect is attributable to constitutive ErbB activity playing a major role in regulating the basal levels pERK. Additional studies support a model in which TGFβ-generated reactive oxygen species serve to indirectly amplify ERK signaling downstream of tonically active ErbBs to mediate EMyT.
Conclusions :
By mechanistically linking TGFβ, ErbB, and ERK signaling to myofibroblast differentiation, our data elucidate a new role for ErbB in the lens and reveal a novel mode by which ERK directs lens cell fate.
This is a 2021 ARVO Annual Meeting abstract.