Dual function of TGFβ in lens epithelial cell fate: Implications for secondary cataract

The most common vision-disrupting complication of cataract surgery is posterior capsule opacifcation (PCO; secondary cataract). PCO is caused by residual lens cells undergoing one of two very different cell fates: either transdifferentiating into myofbroblasts or maturing into lens fber cells. Although TGFβ has been strongly implicated in lens cell fbrosis, the factors responsible for the latter process have not been identifed. We show here for the frst time that TGFβ can induce purifed primary lens epithelial cells within the same culture to undergo differentiation into either lens fber cells or myofbroblasts. Marker analysis confrmed that the two cell phenotypes were mutually exclusive. Blocking the p38 kinase pathway, either with direct inhibitors of the p38 MAP kinase or a small-molecule therapeutic that also inhibits the activation of p38, prevented TGFβ from inducing epithelial-myofbroblast transition and cell migration but did not prevent fber cell differentiation. Rapamycin had the converse effect, linking MTOR signaling to induction of fber cell differentiation by TGFβ. In addition to providing novel potential therapeutic strategies for PCO, our fndings extend the so-called TGFβ paradox, in which TGFβ can induce two disparate cell fates, to a new epithelial disease state.