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J. Funct. Biomater. 2015, 6(2), 222-240; doi:10.3390/jfb6020222

Fibroblastic Transformation of Corneal Keratocytes by Rac Inhibition is Modulated by Extracellular Matrix Structure and Stiffness

Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX 75390-9057, USA
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Author to whom correspondence should be addressed.
Academic Editor: Dimitrios Karamichos
Received: 9 February 2015 / Revised: 6 April 2015 / Accepted: 8 April 2015 / Published: 14 April 2015
(This article belongs to the Special Issue Corneal Disease and Biomaterials)
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Abstract

The goal of this study was to investigate how alterations in extracellular matrix (ECM) biophysical properties modulate corneal keratocyte phenotypes in response to specific wound healing cytokines and Rho GTPases. Rabbit corneal keratocytes were plated within standard collagen matrices (2.5 mg/mL) or compressed collagen matrices (~100 mg/mL) and cultured in serum-free media, PDGF BB, IGF, FGF2 or TGFβ1, with or without the Rac1 inhibitor NSC23766 and/or the Rho kinase inhibitor Y-27632. After 1 to 4 days, cells were labeled for F-actin and imaged using confocal microscopy. Keratocytes within standard collagen matrices (which are highly compliant) maintained a dendritic phenotype following culture in serum-free media, PDGF, IGF and FGF, but developed stress fibers in TGFβ1. Keratocytes within compressed collagen (which has high stiffness and low porosity) maintained a dendritic phenotype following culture in serum-free media, PDGF and IGF, but developed stress fibers in both FGF and TGFβ1. The Rac inhibitor had no significant impact on growth factor responses in compliant matrices. Within compressed collagen matrices however, the Rac inhibitor induced fibroblastic transformation in serum-free media, PDGF and IGF. Fibroblast and myofibroblast transformation was blocked by Rho kinase inhibition. Overall, keratocyte growth factor responses appear to be regulated by both the interplay between Rho and Rac signaling, and the structural and mechanical properties of the ECM. View Full-Text
Keywords: extracellular matrix; biomechanics; corneal keratocytes; growth factors; Rho GTPases extracellular matrix; biomechanics; corneal keratocytes; growth factors; Rho GTPases
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Petroll, W.M.; Lakshman, N. Fibroblastic Transformation of Corneal Keratocytes by Rac Inhibition is Modulated by Extracellular Matrix Structure and Stiffness. J. Funct. Biomater. 2015, 6, 222-240.

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