Abstract
Purpose :
In order to cause vision-disrupting fibrotic PCO, lens epithelial cells that survive cataract surgery must migrate to the posterior of the lens capsule and differentiate into myofibroblasts. During this process, the cells become exposed to the FGF that diffuses out of the vitreous body. In vivo and in vitro studies have established that such relatively high levels of FGF induce lens epithelial cells to differentiate into lens fiber cells during normal development. It has been a mystery as to how epithelial cells could instead undergo a mutually exclusive cell fate, namely epithelial to myofibroblast transition (EMyT), in the FGF-rich environment of the posterior capsule.
Methods :
Western blotting and immunofluorescent microscopy were used to assess the expression of markers of lens cell EMyT in serum-free primary cultures of embryonic chick lens epithelial cells (DCDMLs) grown in the absence or presence of TGFβ and/or FGF. The effect of growth factors on the activation state of ErbBs, AKT, and ERK was assessed using phospho-specific antibodies.
Results :
We have previously shown that the ability of TGFβ to induce lens cell fibrosis requires the activity of endogenous ErbBs. We show here that lens fiber-promoting levels of FGF induce desensitization of the ErbB EGFR1 that involves its phosphorylation on T669 mediated by ERK activity. Transinhibition of EGFR1 by FGF is overcome by a time-dependent increase in expression of total and cell surface EGFR1 induced by TGFβ, the active levels of which are increased after cataract surgery.
Conclusions :
Together, our studies show how a novel integration of TGFβ, FGF, and ErbB signaling pathways can direct EMyT of lens cells under physiologically relevant conditions. They also provide a rationale for why TGFβ upregulates EGFR1 in these cells, and further support the receptor as a therapeutic target for PCO.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.