title: Downregulation of PTEN at corneal wound sites accelerates wound healing through increased cell migration.
abstract: OBJECTIVE
  The PI3K/Akt pathway is required for cell polarization and migration, whereas the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has inhibitory effects on the PI3K/Akt pathway. The authors therefore hypothesized that wounding would downregulate PTEN and that this downregulation would enhance wound healing.
  
  
  METHODS
  In human corneal epithelial (HCE) cell monolayer and rat cornea scratch wound models, the authors investigated PTEN and Akt expression using Western blot and immunofluorescence analyses. The effects of PTEN and PI3K inhibitors dipotassium bisperoxo (picolinato) oxovanadate (bpv(pic)) and LY294002 on cell migration and wound closure were investigated using time-lapse imaging. Finally, the authors investigated the effect of PTEN inhibition on wound healing in whole rat eyes.
  
  
  RESULTS
  In HCE cell monolayer and rat cornea, PTEN was downregulated at the wound edges within 30 minutes of wounding. The downregulation of PTEN was causal in a simultaneous increase in Akt activation, which was responsible for a significant increase in individual cell migration rate from 8.8 μm/h to 17.3 μm/h. An increased migration rate was maintained for 20 hours. PTEN inhibition significantly enhanced the wound healing rate in the HCE cell monolayer from 10 minutes onward after treatment and reduced the healing time in eye organ culture from 30 to 20 hours.
  
  
  CONCLUSIONS
  Injury to the corneal epithelium downregulates the expression of PTEN at wound edges, allowing increased PI3K/Akt signaling, thereby contributing to a significant enhancement of cell migration and wound healing. These results suggest that PTEN inhibition may be an effective treatment for corneal injury.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, California 95817, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Cao
authors.forename: Enrique O
authors.initials: EO
authors.lastname: Graue-Hernandez
authors.forename: Vu
authors.initials: V
authors.lastname: Tran
authors.forename: Brian
authors.initials: B
authors.lastname: Reid
authors.forename: Jin
authors.initials: J
authors.lastname: Pu
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mannis
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019573:Epithelium, Corneal / Q000166:cytology* / Q000201:enzymology; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009924:Organ Culture Techniques; D009942:Organometallic Compounds / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000502:physiology*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009942:Organometallic Compounds; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C119540:oxodiperoxo(pyridine-2-carboxylate)vanadate(V); C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494929:PTEN protein, human; C487216:Pten protein, rat