TGF-α/HA complex promotes tympanic membrane keratinocyte migration and proliferation via ErbB1 receptor

Exp Cell Res. 2013 Apr 1;319(6):790-9. doi: 10.1016/j.yexcr.2013.01.015. Epub 2013 Feb 4.

Abstract

Tympanic membrane perforations are common and represent a management challenge to clinicians. Current treatments for chronic perforations involve a graft surgery and require general anaesthesia, including associated costs and morbidities. Bioactive molecules (e.g. growth factors, cytokines) play an important role in promoting TM wound healing following perforation and the use of growth factors as a topical treatment for tympanic membrane perforations has been suggested as an alternative to surgery. However, the choice of bioactive molecules best suited to promote wound healing has yet to be identified. We investigated the effects of hyaluronic acid, vitronectin, TGF-α, IL-24 and their combinations on migration, proliferation and adhesion of cultured human tympanic membrane-derived keratinocytes (hTM), in addition to their possible mechanisms of action. We found that TGF-α, TGF-α/HA and TGF-α/IL-24 promoted wound healing by significantly increasing both migration and proliferation. TGF-α and/or HA treated cells showed comparable cell-cell adhesion whilst maintaining an epithelial cell phenotype. With the use of receptor binding inhibitors for ErbB1 (AG1478) and CD44 (BRIC235), we revealed that the activation of ErbB1 is required for TGF-α/HA-mediated migration and proliferation. These results suggest factors that may be incorporated into a tissue-engineered membrane or directly as topical treatment for tympanic membrane perforations and hence reduce the need for a surgery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Adhesion / drug effects
  • Cell Migration Assays
  • Cell Movement / drug effects*
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Humans
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / pharmacology*
  • Interleukins / pharmacology
  • Keratinocytes / cytology*
  • Keratinocytes / drug effects
  • Phenotype
  • Quinazolines / pharmacology
  • Transforming Growth Factor alpha / pharmacology*
  • Tympanic Membrane / cytology*
  • Tympanic Membrane / drug effects
  • Tympanic Membrane / metabolism
  • Tyrphostins / pharmacology
  • Vitronectin / pharmacology

Substances

  • CD44 protein, human
  • Cadherins
  • Hyaluronan Receptors
  • Interleukins
  • Quinazolines
  • Transforming Growth Factor alpha
  • Tyrphostins
  • Vitronectin
  • interleukin-24
  • RTKI cpd
  • Hyaluronic Acid
  • ErbB Receptors