title: Delayed loss of corneal epithelial stem cells in a chemical injury model associated with limbal stem cell deficiency in rabbits.
abstract: OBJECTIVE
  Ocular injuries following exposure to the chemical agent sulfur mustard (SM) are characterized by acute corneal erosions and inflammation of the anterior segment that may be followed by delayed Partial Limbal Stem Cell Deficiency (LSCD), expressed clinically by corneal neovascularization and epithelial defects. LSCD may derive from direct destruction of limbal stem cells or indirectly from altered limbal stromal niche. The aim of this study was to investigate the mechanism underlying LSCD in SM injuries, focusing on the effects of the chemical on limbal epithelium.
  
  
  METHODS
  Rabbit eyes were exposed to SM vapor and were observed by slit lamp examinations and pachymetry. Eyes were taken for histological and molecular biology evaluations at different time points (4 h-4 weeks), to include acute and delayed injuries. Epithelial stem cells were identified by ABCG2, p63 and by in vivo BrdU labeling for slow cycling cells.
  
  
  RESULTS
  Limbal stem cells were not damaged during the acute phase following SM exposure, in contrast to the severe injury of the central corneal epithelium. On the contrary, limbal epithelium became activated, responding to corneal insult with a wound healing process, as shown by histology and by transient elevation of the stem cells markers. Simultaneously, inflammation was taking place in the limbal stroma lasting for weeks. A gradual loss of stem cells was observed later-on (2-4 weeks), associated with typical symptoms of LSCD.
  
  
  CONCLUSIONS
  LSCD associated with SM ocular toxicity was not derived from a direct cytotoxic effect on the epithelial stem cells, but apparently from pathological events at the limbal stroma, that produced an abnormal microenvironment for the stem cells, triggering their gradual death. The results, and in particular the absence of a primary damage to the epithelial stem cells, indicate the presence of a therapeutic window for intervention to avoid the development of the delayed LSCD.
authors: Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, Israel. tamark@iibr.gov.il
authors: Tamar
authors: T
authors: Kadar
authors: Vered
authors: V
authors: Horwitz
authors: Rita
authors: R
authors: Sahar
authors: Maayan
authors: M
authors: Cohen
authors: Liat
authors: L
authors: Cohen
authors: Rellie
authors: R
authors: Gez
authors: Liat
authors: L
authors: Tveria
authors: Hila
authors: H
authors: Gutman
authors: Hillel
authors: H
authors: Buch
authors: Eliezer
authors: E
authors: Fishbine
authors: Rachel
authors: R
authors: Brandeis
authors: Shlomit
authors: S
authors: Dachir
authors: Adina
authors: A
authors: Amir
mesh_terms: D000818:Animals; D002057:Burns, Chemical / Q000473:pathology*; D002452:Cell Count; D002453:Cell Cycle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019573:Epithelium, Corneal / Q000293:injuries / Q000473:pathology*; D005126:Eye Burns / Q000139:chemically induced / Q000473:pathology*; D005260:Female; D016850:Limbus Corneae / Q000293:injuries / Q000473:pathology*; D011817:Rabbits; D013234:Stem Cells / Q000473:pathology*