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The Role of Extracellular Matrix in Corneal Wound Healing

Yamanaka, Osamu MD, PhD; Sumioka, Takayoshi MD, PhD; Saika, Shizuya MD, PhD

doi: 10.1097/ICO.0b013e3182a4786b

Abstract: During wound healing, cell migration, proliferation, differentiation, and enhanced biosynthetic activities are observed at the sites of injury. Interactions between extracellular matrix (ECM) components and specific cell surface receptors, such as integrins, initiate cascades of signal transduction leading to various cellular responses. This review will focus on the biological functions of several ECM components, such as osteopontin (OPN), tenascin (TCN), and lumican (Lum). The loss of OPN or TCN reduces macrophage invasion and myofibroblast differentiation in the healing stroma and is associated with the suppression of fibrogenic gene expression in response to injury sustained in mice. Gene expression analysis showed that the lack of OPN or TCN resulted in the inhibition of proinflammatory and fibrogenic gene expression. It has been shown that Lum also modulates cell adhesion, migration, and proliferation, thus contributing to corneal epithelial wound healing. Interestingly, OPN-, TCN-, or Lum-null mice had reduced Smad activity and epithelial–mesenchymal transitions. Smads are nuclear effectors of transforming growth factor-β and regulate transcription. However, it is still not clear as to how individual ECM components initiate the signaling pathway. We hypothesized that a cell surface receptor for these ECM components may mediate the matrikine functions of Lum. To identify the specific receptor for Lum, we developed purified recombinant glutathione S-transferase–Lum. Using this, we identified a potential receptor for Lum that modulated wound healing.

Department of Ophthalmology, Wakayama Medical University, Kimiidera, Japan.

Reprints: Osamu Yamanaka, Department of Ophthalmology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan (e-mail:

The authors received financial support from Santen Pharmaceutical (Osaka, Japan) to prepare this article.

Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.