title: Dual function of TGFβ in lens epithelial cell fate: implications for secondary cataract.
abstract: The most common vision-disrupting complication of cataract surgery is posterior capsule opacification (PCO; secondary cataract). PCO is caused by residual lens cells undergoing one of two very different cell fates: either transdifferentiating into myofibroblasts or maturing into lens fiber cells. Although TGFβ has been strongly implicated in lens cell fibrosis, the factors responsible for the latter process have not been identified. We show here for the first time that TGFβ can induce purified primary lens epithelial cells within the same culture to undergo differentiation into either lens fiber cells or myofibroblasts. Marker analysis confirmed 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-myofibroblast transition and cell migration but did not prevent fiber cell differentiation. Rapamycin had the converse effect, linking MTOR signaling to induction of fiber cell differentiation by TGFβ. In addition to providing novel potential therapeutic strategies for PCO, our findings extend the so-called TGFβ paradox, in which TGFβ can induce two disparate cell fates, to a new epithelial disease state.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Boswell
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Korol
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University Health Science Centre, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Judith A
authors.initials: JA
authors.lastname: West-Mays
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239 musill@OHSU.edu.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Musil
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D006801:Humans; D007908:Lens, Crystalline / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000502:physiology*
chemical_list: D005136:Eye Proteins; D016212:Transforming Growth Factor beta