title: Role of thrombospondin-1 in repair of penetrating corneal wounds.
abstract: OBJECTIVE
  Thrombospondin-1 (THBS1) has been suggested as a corneal wound-healing modulator. Therefore, we compromised the integrity of the cornea to elucidate the role of THBS1.
  
  
  METHODS
  Full-thickness penetrating corneal incisions (1.5 mm) were created in wild type (WT, 129S2/SvPas) and THBS1-deficient mice (Thbs1⁻/⁻), 129S2/SvPas-Thbs1(tm1Hyn)/Thbs1(tm1Hyn)), and allowed to heal up to 1 month, while being monitored by slit-lamp and intravital corneal examinations. Corneas also were examined by transmission electron microscopy and indirect immunofluorescence. To determine how THBS1 was involved in the healing process, we examined THBS1 and α-smooth muscle actin (SMA), a marker of myofibroblasts and myoepithelial cells.
  
  
  RESULTS
  In WT mice by 1 month, corneas appeared transparent with a thin scar, and endothelium and Descemet's membrane (DM) were restored. In contrast, Thbs1⁻/⁻ corneas exhibited chronic edema and persistent opacity after wounding. The DM and endothelium were not restored, and wound contraction was impaired. The THBS1 was localized in epithelial cells at early stages of the healing process, and in the stroma and endothelial cells during later stages. The SMA-positive epithelial cells and myofibroblasts were observed within the healing area at day 4, peaked at day 14, and disappeared at day 30. The SMA-positive cells were reduced greatly in Thbs1⁻/⁻ mice.
  
  
  CONCLUSIONS
  In the current study, we demonstrated that corneal restoration is strikingly compromised by a penetrating incision in Thbs1⁻/⁻ mice. The wound results in persistent edema and wound gaping. This appears to be the result of the lack of endothelial migration and DM restoration. In addition, myofibroblast formation is compromised, resulting in the lack of wound contraction.
authors: Schepens Eye Research Institute/Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors: José Tomás
authors: JT
authors: Blanco-Mezquita
authors: Audrey E K
authors: AE
authors: Hutcheon
authors: James D
authors: JD
authors: Zieske
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D057112:Corneal Perforation / Q000473:pathology / Q000503:physiopathology*; D003319:Corneal Stroma / Q000378:metabolism; D004195:Disease Models, Animal; D004728:Endothelium, Corneal / Q000378:metabolism; D015807:Eye Injuries, Penetrating / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D058628:Myofibroblasts / Q000166:cytology; D019700:Thrombospondin 1 / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000199:Actins; D019700:Thrombospondin 1; C544013:alpha-smooth muscle actin, mouse
keywords: corneal epithelium; corneal wound healing; endothelial restoration; penetrating wound; thrombospondin-1
references: Invest Ophthalmol Vis Sci. 1992 Nov;33(12):3292-301
references: 1428704
references: Trans Am Ophthalmol Soc. 2002;100:411-33
references: 12545703
references: Cornea. 1998 Nov;17(6):627-39
references: 9820944
references: Clin Exp Ophthalmol. 2006 Nov;34(8):797-9
references: 17073905
references: Invest Ophthalmol Vis Sci. 2001 Oct;42(11):2490-5
references: 11581188
references: Prog Retin Eye Res. 1999 May;18(3):311-56
references: 10192516
references: Am J Pathol. 2002 Sep;161(3):831-9
references: 12213711
references: Biochem Biophys Res Commun. 2004 Mar 19;315(4):928-34
references: 14985101
references: Invest Ophthalmol Vis Sci. 1986 Jan;27(1):44-51
references: 3941037
references: Invest Ophthalmol Vis Sci. 2012 Sep 28;53(10):6708-17
references: 22930728
references: Proc Natl Acad Sci U S A. 1971 Jan;68(1):240-3
references: 5276296
references: Invest Ophthalmol Vis Sci. 2002 Sep;43(9):2897-904
references: 12202508
references: N Engl J Med. 1993 Jun 24;328(25):1828-35
references: 8502273
references: Histol Histopathol. 2005 Apr;20(2):493-9
references: 15736054
references: Invest Ophthalmol Vis Sci. 2005 Mar;46(3):908-19
references: 15728547
references: Mol Biol Cell. 1992 Feb;3(2):181-8
references: 1550960
references: Cell Tissue Res. 1997 Aug;289(2):307-10
references: 9211833
references: Cornea. 1997 Mar;16(2):177-87
references: 9071531
references: J Clin Invest. 2001 Apr;107(8):929-34
references: 11306593
references: Microvasc Res. 2009 Jan;77(1):13-20
references: 18952113
references: EMBO J. 2000 Jul 3;19(13):3272-82
references: 10880440
references: Prog Retin Eye Res. 2006 Jan;25(1):1-18
references: 15996506
references: Histol Histopathol. 1999 Oct;14(4):1309-20
references: 10506946
references: J Clin Invest. 1984 Nov;74(5):1764-72
references: 6501568
references: Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1775-88
references: 15161840
references: J Cell Physiol. 1989 Nov;141(2):392-9
references: 2808545
references: J Biol Chem. 1993 Dec 15;268(35):26784-9
references: 8253815
references: J Mammary Gland Biol Neoplasia. 1996 Oct;1(4):353-63
references: 10887509
references: Cell Mol Life Sci. 2008 Mar;65(5):672-86
references: 18193164
references: Eur J Cell Biol. 1990 Aug;52(2):252-63
references: 2081528
references: Curr Opin Cell Biol. 2000 Oct;12(5):634-40
references: 10978901
references: Am J Pathol. 2009 Sep;175(3):1136-47
references: 19700744
references: Lab Invest. 1990 Jul;63(1):21-9
references: 2197503
references: J Cell Commun Signal. 2009 Dec;3(3-4):189-200
references: 19798599
references: Prog Retin Eye Res. 2000 May;19(3):257-70
references: 10749377
references: Exp Eye Res. 2001 Jan;72(1):33-9
references: 11133180
references: J Cell Biol. 1993 Jul;122(1):103-11
references: 8314838
references: Mol Vis. 2008;14:2272-81
references: 19081766
references: Invest Ophthalmol Vis Sci. 2002 Jul;43(7):2152-9
references: 12091410
references: Invest Ophthalmol Vis Sci. 1998 Oct;39(11):1981-9
references: 9761276
references: Exp Eye Res. 2011 Oct;93(4):534-40
references: 21749870
references: Am J Ophthalmol. 2011 Oct;152(4):537-542.e2
references: 21726845
references: Histol Histopathol. 1999 Jan;14(1):285-94
references: 9987673
references: Invest Ophthalmol Vis Sci. 2006 Apr;47(4):1352-8
references: 16565368
references: Mol Vis. 2007 Aug 27;13:1483-95
references: 17893672
references: Mol Biol Cell. 1999 May;10(5):1537-51
references: 10233161
references: Dev Biol. 1984 Jan;101(1):212-20
references: 6692974
references: Crit Rev Clin Lab Sci. 1987;25(2):161-93
references: 3301214
references: J Cell Biol. 1987 Nov;105(5):2409-15
references: 3680388
references: J Biol Chem. 2004 Sep 3;279(36):38032-9
references: 15208302
references: J Clin Invest. 1998 Mar 1;101(5):982-92
references: 9486968