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* Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York; and
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York
1Correspondence: Department of Ophthalmology, Box 1183, Mt. Sinai School of Medicine, 1 Gustave Levy Pl., New York, NY 10029-6574, USA. E-mail: roseanne.greenberg{at}mssm.edu
ABSTRACT
Fibroblasts and myofibroblasts both participate in wound healing. Transforming growth factor beta (TGFß) induces fibroblasts to differentiate into myofibroblasts, whereas fibroblast growth factor and heparin (FGF/h) induce myofibroblasts to "de-differentiate" into fibroblasts. TGFß induces expression of smooth muscle alpha actin (SM
A) and incorporation into in stress fibers, a phenotype of differentiated myofibroblasts. Additionally, TGFß induces the expression of fibronectin and fibronectin integrins. Fibronectin-generated signals contribute to the TGFß-mediated myofibroblast differentiation. Because fibronectin signals are transmitted through focal adhesion kinase (FAK), it was predicted that FAK would be essential to TGFß-mediated myofibroblast differentiation. To determine whether the FAK signaling pathway is required for myofibroblast differentiation, we used two approaches to decrease FAK in mouse embryo fibroblasts (MEFs): 1) FAK +/+ MEFs, in which FAK protein expression was greatly decreased by short hairpin RNA (shRNA), and 2) FAK –/– MEFs, which lack FAK. In both cases, the majority of cells were myofibroblasts, expressing SMA in stress fibers even after treatment with FGF/h. Furthermore, both the surface expression of FGFRs and FGF signaling were greatly reduced in FAK–/– MEFs. We conclude that FAK does not contribute to TGFß-dependent myofibroblast differentiation. Instead, FAK was necessary for FGF/h signaling in down-regulating expression of SMA, which is synonymous with myofibroblast differentiation. FAK activation could contribute to regulating myofibroblast differentiation, thereby ameliorating fibrosis.—Greenberg, R. S., Bernstein, A. M., Benezra, M., Gelman, I. H., Taliana, L., Masur, S. K. FAK-DEPENDENT REGULATION OF MYOFIBROBLAST DIFFERENTIATION.
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