角膜基质创伤愈合的研究进展

doi:10.6040/j.issn.1671-9352.0.2016.079

摘要/Abstract

摘要： 角膜基质创伤愈合是一个涉及细胞调亡、迁移、增殖、分化和细胞外基质重建的复杂过程。转化生长因子β(TGF-β)系统在调控角膜基质细胞转化和基质纤维化方面具有关键作用,其失调是造成愈合后形成基质瘢痕、出现雾状混浊和视力受损的主要原因。近年来,在角膜基质创伤愈合的研究方面取得了重要进展,并开发出了一些消除基质瘢痕的新的治疗方法。本文拟围绕角膜基质的创伤愈合过程,细胞表型转化及其调控因子,以及愈合过度的控制策略进行综述。

关键词: 角膜基质, 雾状混浊, 基质瘢痕, 角膜基质细胞, 创伤愈合

Abstract: Corneal stroma wound healing is a complex process involving cell apoptosis, migration, proliferation, differentiation, and extracellular matrix remodeling. Transforming growth factor β(TGF-β)system plays central roles in regulating the transformation of stromal cells and the fibrosis of stroma, and its dysregulation might be the main cause of stromal haze, scar formation and vision damage. Recently, great progress has been made in the study of corneal stromal wound healing, and various new therapies to attenuate stromal scar have also been developed. The process of corneal stromal wound healing, cellular phenotype transformation and its regulating factors, and strategies of excessive healing control are reviewed.

Key words: corneal stroma, haze, stromal scar, keratocyte, wound healing

中图分类号:

R772.2

樊廷俊,白苏冉. 角膜基质创伤愈合的研究进展[J]. 山东大学学报（理学版）, 2016, 51(3): 1-10.

FAN Ting-jun, BAI Su-ran. Research progress of corneal stromal wound healing[J]. JOURNAL OF SHANDONG UNIVERSITY(NATURAL SCIENCE), 2016, 51(3): 1-10.

参考文献

[1] MEEK K M, KNUPP C. Corneal structure and transparency[J]. Prog Retin Eye Res, 2015, 49:1-16.
[2] LJUBIMOV A V, SAGHIZADEH M. Progress in corneal wound healing[J]. Prog Retin Eye Res, 2015, 49:17-45.
[3] NETTO M V, MOHAN R R, AMBRÓSIO R JR, et al. Wound healing in the cornea: a review of refractive surgery complications and new prospects for therapy[J]. Cornea, 2005, 24(5):509-522.
[4] FINI M E, STRAMER B M. How the cornea heals: cornea-specific repair mechanisms affecting surgical outcomes[J]. Cornea, 2005, 24(8):S2-11.
[5] 赵文卓, 樊廷俊, 胡修忠, 等. 组织工程人角膜基质体外重建的研究进展[J]. 山东大学学报(医学版), 2011, 49(8):62-66. ZHAO Wenzhuo, FAN Tingjun, HU Xiuzhong, et al. Research advances on in vitro reconstruction of tissue-engineered human corneal stroma[J]. Journal of Shandong University( Medical Science), 2011, 49(8):62-66.
[6] MICHELACCI Y M. Collagens and proteoglycans of the corneal extracellular matrix[J]. Braz J Med Biol Res, 2003, 36(8):1037-1046.
[7] JESTER J V, MOLLER-PEDERSEN T, HUANG J, et al. The cellular basis of corneal transparency: evidence for ‘corneal crystallins’ [J]. J Cell Sci, 1999, 112(Pt5):613-622.
[8] 樊廷俊, 胡修忠, 葛源. 人类角膜基质细胞研究进展[J]. 山东大学学报(医学版), 2012, 50(8), 57-61. FAN Tingjun, HU xiuzhong, GE Yuan. Research progress in human corneal keratocytes[J]. Journal of Shandong University(Medical Science), 2012, 50(8), 57-61.
[9] TORRICELLI A A, SANTHANAM A, WU J, et al. The corneal fibrosis response to epithelial-stromal injury[J]. Exp Eye Res, 2016, 142:110-118.
[10] Wilson S E, He Y G, Weng J, et al. Epithelial injury induces keratocyte apoptosis: hypothesized role for the interleukin-1 system in the modulation of corneal tissue organization and wound healing[J]. Exp Eye Res, 1996, 62(4):325-327.
[11] MAYCOCK N J, MARSHALL J. Genomics of corneal wound healing: a review of the literature[J]. Acta Ophthalmol, 2014, 92(3):e170-184.
[12] WEST-MAYS J A, DWIVEDI D J. The keratocyte: Corneal stromal cell with variable repair phenotypes[J]. Int J Biochem Cell Biol, 2006, 38(10):1625-1631.
[13] ZIESKE J D. Extracellular matrix and wound healing[J]. Curr Opin Ophthalmol, 2001, 12(4):237-241.
[14] WILSON S E, CHAURASIA S S, MEDEIROS F W. Apoptosis in the initiation, modulation and termination of the corneal wound healing response[J]. Exp Eye Res, 2007, 85(3):305-311.
[15] JESTER J V, HO-CHANG J. Modulation of cultured corneal keratocyte phenotype by growth factors/cytokines control in vitro contractility and extracellular matrix contraction[J]. Exp Eye Res, 2003, 77(5):581-592.
[16] WILSON S L, EL HAJ A J, YANG Y. Control of scar tissue formation in the cornea: strategies in clinical and corneal tissue engineering[J]. J Funct Biomater, 2012, 3(3):642-687
[17] FINI M E. Keratocyte and fibroblast phenotypes in the repairing cornea[J]. Prog Retin Eye Res, 1999, 18(4):529-551.
[18] CARLSON E C, WANG I J, LIU C Y, et al. Altered KSPG expression by keratocytes following corneal injury[J]. Mol Vis, 2003, 9:615-623.
[19] JESTER J V, PETROLL W M, CAVANAGH H D. Corneal stromal wound healing in refractive surgery: the role of myofibroblasts[J]. Prog Retin Eye Res, 1999, 18(3):311-356.
[20] CHAURASIA S S, KAUR H, DE MEDEIROS F W, et al. Reprint of “Dynamics of the expression of intermediate filaments vimentin and desmin during myofibroblast differentiation after corneal injury”[J]. Exp Eye Res, 2009, 89(4):590-596.
[21] KAUR H, CHAURASIA S S, AGRAWAL V, et al. Corneal myofibroblast viability: opposing effects of IL-1 and TGF beta1[J]. Exp Eye Res, 2009, 89(2):152-158.
[22] SINGH V, BARBOSA F L, TORRICELLI A A, et al. Transforming growth factor β and platelet-derived growth factor modulation of myofibroblast development from corneal fibroblasts in vitro[J]. Exp Eye Res, 2014, 120:152-160.
[23] KARAMICHOS D HUTCHEON A E, ZIESKE J D. Reversal of fibrosis by TGF-β3 in a 3D in vitro model[J]. Exp Eye Res, 2014, 124:31-36.
[24] JESTER J V, PETROLL W M, BARRY P A, et al. Expression of alpha-smooth muscle(alpha-SM)actin during corneal stromal wound healing[J]. Invest Ophthalmol Vis Sci, 1995, 36(5):809-819.
[25] BARBOSA F L, CHAURASIA S S, CUTLER A, et al. Corneal myofibroblast generation from bone marrow-derived cells[J]. Exp Eye Res, 2010, 91(1):92-96.
[26] SINGH V, AGRAWAL V, SANTHIAGO M R, et al Stromal fibroblast-bone marrow-derived cell interactions: implications for myofibroblast development in the cornea[J]. Exp Eye Res, 2012, 98:1-8.
[27] RUIZ-EDERRA J, VERKMAN A S. Aquaporin-1-facilitated keratocyte migration in cell culture and in vivo corneal wound healing models[J]. Exp Eye Res, 2009, 89(2):159-165.
[28] SINGH V, TORRICELLI A A, NAYEB-HASHEMI N, et al. Mouse strain variation in SMA(+)myofibroblast development after corneal injury[J]. Exp Eye Res, 2013, 115:27-30.
[29] GAN L, FAGERHOLM P, KIM H J. Effect of leukocytes on corneal cellular proliferation and wound healing[J]. Invest Ophthalmol Vis Sci, 1999, 40(3):575-581.
[30] WILSON S E, MOHAN R R, MOHAN R R, et al. The corneal wound healing response: cytokine-mediated interaction of the epithelium, stroma, and inflammatory cells[J]. Prog Retin Eye Res, 2001, 20(5):625-637.
[31] LIU Q, SMITH C W, ZHANG W, et al. NK cells modulate the inflammatory response to corneal epithelial abrasion and thereby support wound healing[J]. Am J Pathol, 2012, 181(2):452-462.
[32] LI S, LI B, JIANG H, et al. Macrophage depletion impairs corneal wound healing after autologous transplantation in mice[J]. PLoS One, 2013, 8(4):e61799.
[33] MAYER W J, KLAPROTH O K, HENGERER F H, et al. In vitro immunohistochemical and morphological observations of penetrating corneal incisions created by a femtosecond laser used for assisted intraocular lens surgery[J]. J Cataract Refract Surg, 2014, 40(4):632-638.
[34] HAYASHI Y, CALL M K, CHIKAMA T, et al. Lumican is required for neutrophil extravasation following corneal injury and wound healing[J]. J Cell Sci, 2010, 123(Pt17):2987-2995.
[35] TORRICELLI A A, WILSON S E. Cellular and extracellular matrix modulation of corneal stromal opacity[J]. Exp Eye Res, 2014, 129:151-160.
[36] MAGUEN E, RABINOWITZ Y S, REGEV L, et al. Alterations of extracellular matrix components and proteinases in human corneal buttons with INTACS for post-laser in situ keratomileusis keratectasia and keratoconus[J]. Cornea, 2008, 27(5):565-573.
[37] KATO T, CHANG J H, AZAR D T. Expression of type XVIII collagen during healing of corneal incisions and keratectomy wounds[J]. Invest Ophthalmol Vis Sci, 2003, 44(1):78-85.
[38] ISHIZAKI M, SHIMODA M, WAKAMATSU K, et al. Stromal fibroblasts are associated with collagen IV in scar tissues of alkali-burned and lacerated corneas[J]. Curr Eye Res, 1997, 16(4):339-348.
[39] MELLES G R, SUNDARRAJ N, BINDER P S, et al. Immunohistochemical analysis of unsutured and sutured corneal wound healing[J]. Curr Eye Res, 1995, 14(9):809-817.
[40] NICKELEIT V, KAUFMAN A H, ZAGACHIN L, et al. Healing corneas express embryonic fibronectin isoforms in the epithelium, subepithelial stroma, and endothelium[J]. Am J Pathol, 1996, 149(2):549-558.
[41] MATSUBA M, HUTCHEON A E, ZIESKE J D. Localization of thrombospondin-1 and myofibroblasts during corneal wound repair[J]. Exp Eye Res, 2011, 93(4):534-450.
[42] SAIKA S, SUMIOKA T, OKADA Y, et al. Wakayama symposium: modulation of wound healing response in the corneal stroma by osteopontin and tenascin-C[J]. Ocul Surf, 2013, 11(1):12-15.
[43] CHAURASIA S S, PERERA P R, POH R, et al. Hevin plays a pivotal role in corneal wound healing[J]. PLoS One, 2013, 8(11):e81544.1- e81544.15.
[44] MIYAZAKI K, OKADA Y, YAMANAKA O, et al. Corneal wound healing in an osteopontin-deficient mouse[J]. Invest Ophthalmol Vis Sci, 2008, 49(4):1367-1375.
[45] SUMIOKA T, KITANO A, FLANDERS K C, et al. Impaired cornea wound healing in a tenascin C-deficient mouse model[J]. Lab Invest, 2013, 93(2):207-217.
[46] BLANCO-MEZQUITA J T, HUTCHEON A E, ZIESKE J D. Role of thrombospondin-1 in repair of penetrating corneal wounds[J]. Invest Ophthalmol Vis Sci, 2013, 54(9):6262-6268.
[47] BALDWIN H C, MARSHALL J. Growth factors in corneal wound healing following refractive surgery: a review[J]. Acta Ophthalmol Scand, 2002, 80(3):238-247.
[48] CARRINGTON L M, BOULTON M. Hepatocyte growth factor and keratinocyte growth factor regulation of epithelial and stromal corneal wound healing[J]. J Cataract Refract Surg, 2005, 31(2):412-423.
[49] KAKAZU A, HE J, KENCHEGOWDA S, et al. Lipoxin A₄ inhibits platelet-activating factor inflammatory response and stimulates corneal wound healing of injuries that compromise the stroma[J]. Exp Eye Res, 2012, 103:9-16.
[50] MALECAZE F, MASSOUDI D, FOURNIÉ P, et al. Upregulation of bone morphogenetic protein-1/mammalian tolloid and procollagen C-proteinase enhancer-1 in corneal scarring[J]. Invest Ophthalmol Vis Sci, 2014, 55(10):6712-6721.
[51] IZUMI K, KUROSAKA D, IWATA T, et al. Involvement of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in corneal fibroblasts during corneal wound healing[J]. Invest Ophthalmol Vis Sci, 2006, 47(2):591-598.
[52] SHI L, CHANG Y, YANG Y, et al. Activation of JNK signaling mediates connective tissue growth factor expression and scar formation in corneal wound healing[J]. PLoS One, 2012, 7(2):e32128.1- e32128.9.
[53] HUXLIN K R, HINDMAN H B, JEON K I, et al. Topical rosiglitazone is an effective anti-scarring agent in the cornea[J]. PLoS One, 2013, 8(8):e70785.1- e70785.16.
[54] MØLLER-PEDERSEN T, CAVANAGH H D, PETROLL W M, et al. Neutralizing antibody to TGFbeta modulates stromal fibrosis but not regression of photoablative effect following PRK[J]. Curr Eye Res, 1998, 17(7):736-747.
[55] JUNG J C, HUH M I, FINI M E. Constitutive collagenase-1 synthesis through MAPK pathways is mediated, in part, by endogenous IL-1alpha during fibrotic repair in corneal stroma[J]. J Cell Biochem, 2007, 102(2):453-462.
[56] MILANI B Y, MILANI F Y, PARK D W, et al. Rapamycin inhibits the production of myofibroblasts and reduces corneal scarring after photorefractive keratectomy[J]. Invest Ophthalmol Vis Sci, 2013, 54(12):7424-7430.
[57] LEE S H, LEEM H S, JEONG S M, et al. Bevacizumab accelerates corneal wound healing by inhibiting TGF-beta2 expression in alkali-burned mouse cornea[J]. BMB Rep, 2009, 42(12):800-805.
[58] CHEN J, GUERRIERO E, SADO Y, et al. Rho-mediated regulation of TGF-beta1- and FGF-2-induced activation of corneal stromal keratocytes[J]. Invest Ophthalmol Vis Sci, 2009, 50(8):3662-3670.
[59] SHARMA A, MEHAN M M, SINHA S, et al. Trichostatin A inhibits corneal haze in vitro and in vivo[J]. Invest Ophthalmol Vis Sci, 2009, 50(6):2695-2701.
[60] ALIO J L, ARNALICH-MONTIEL F, RODRIGUEZ A E. The role of “eye platelet rich plasma”(E-PRP)for wound healing in ophthalmology[J]. Curr Pharm Biotechnol, 2012, 13(7):1257-1265.
[61] ANITUA E, SANCHEZ M, MERAYO-LLOVES J, et al. Plasma rich in growth factors(PRGF-Endoret)stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation[J]. Invest Ophthalmol Vis Sci, 2011, 52(9):6066-6073.
[62] ANITUA E, MURUZABAL F, ALCALDE I, et al. Plasma rich in growth factors(PRGF-Endoret)stimulates corneal wound healing and reduces haze formation after PRK surgery[J]. Exp Eye Res., 2013, 115:153-161.
[63] DAS S K, GUPTA I, CHO Y K, et al. Vimentin knockdown decreases corneal opacity[J]. Invest Ophthalmol Vis Sci, 2014, 55(7):4030-4040.
[64] MOHAN R R, GUPTA R, MEHAN M K, et al. Decorin transfection suppresses profibrogenic genes and myofibroblast formation in human corneal fibroblasts[J]. Exp Eye Res, 2010, 91(2):238-245.
[65] MOHAN R R, TANDON A, SHARMA A, et al. Significant inhibition of corneal scarring in vivo with tissue-selective, targeted AAV5 decorin gene therapy[J]. Invest Ophthalmol Vis Sci, 2011, 52(7):4833-4841.
[66] TANDON A, SHARMA A, RODIER J T, et al. BMP7 gene transfer via gold nanoparticles into stroma inhibits corneal fibrosis in vivo[J]. PLoS One, 2013, 8(6):e66434.1-. e66434.9
[67] SRIRAM S, GIBSON D J, ROBINSON P, et al. Assessment of anti-scarring therapies in ex vivo organ cultured rabbit corneas[J]. Exp Eye Res, 2014, 125:173-182.
[68] CHOWDHURY S, GUHA R, TRIVEDI R, et al. Pirfenidone nanoparticles improve corneal wound healing and prevent scarring following alkali burn[J]. PLoS One, 2013, 8(8):e70528.1- e70528.10.
[69] QAZI Y, STAGG B, SINGH N, et al. Nanoparticle-mediated delivery of shRNA.VEGF-a plasmids regresses corneal neovascularization[J]. Invest Ophthalmol Vis Sci, 2012, 53(6):2837-2844.
[70] DU Y, FUNDERBURGH M L, MANN M M, et al. Multipotent stem cells in human corneal stroma[J]. Stem Cells, 2005, 23(9):1266-1275.
[71] DU Y, CARLSON E C, FUNDERBURGH M L, et al. Stem cell therapy restores transparency to defective murine corneas[J]. Stem Cells, 2009, 27(7):1635-1642.
[72] THILL M, SCHLAGNER K, ALTENÄHR S, et al. A novel population of repair cells identified in the stroma of the human cornea[J]. Stem Cells Dev, 2007, 16(5):733-745.
[73] BASU S, HERTSENBERG A J, FUNDERBURGH M L, et al. Human limbal biopsy-derived stromal stem cells prevent corneal scarring[J]. Sci Transl Med, 2014, 6(266):266ra172.1-266ra172.11.
[74] MA X Y, BAO H J, CUI L, et al. The graft of autologous adipose-derived stem cells in the corneal stromal after mechanic damage[J]. PLoS One, 2013, 8(10):e76103.1- e76103.12.
[75] WU J, DU Y, MANN M M, et al. Corneal stromal stem cells versus corneal fibroblasts in generating structurally appropriate corneal stromal tissue[J]. Exp Eye Res, 2014, 120:71-81.
[76] GRIFFITH M, HARKIN D G. Recent advances in the design of artificial corneas[J]. Curr Opin Ophthalmol, 2014, 25(3):240-247.
[77] HONG J, XU J, SUN X, et al. Tissue-engineered corneal stroma by using autologous adipose derived stem cell tissue and polylacticcocglycolic acid[J]. IFMBE Proc, 2009, 25(11):1-5.
[78] DIAO J M, PANG X, QIU Y, et al. Construction of a human corneal stromal equivalent with non-transfected human corneal stromal cells and acellular porcine corneal stromata[J]. Exp Eye Res, 2015,132:216-224.
[79] KOULIKOVSKA M, RAFAT M, PETROVSKI G, et al. Enhanced regeneration of corneal tissue via a bioengineered collagen construct implanted by a nondisruptive surgical technique[J]. Tissue Eng Part A, 2015, 21(5/6):1116-1130.
[80] KURESHI A K, DRAKE R A, DANIELS J T. Challenges in the development of a reference standard and potency assay for the clinical production of RAFT tissue equivalents for the cornea[J]. Regen Med, 2014, 9(2):167-177.
[81] ZHOU Q, LIU Z, WU Z, et al. Reconstruction of highly proliferative auto-tissue-engineered lamellar cornea enhanced by embryonic stem cell[J]. Tissue Eng Part C Methods, 2015, 21(7):639-648.
[82] PROULX S, DARC UWAMALIYA J, CARRIER P, et al. Reconstruction of a human cornea by the self-assembly approach of tissue engineering using the three native cell types[J]. Mol Vis, 2010, 16:2192-2201.
[83] MELTENDORF C, BURBACH G J, OHRLOFF C, et al. Intrastromal keratotomy with femtosecond laser avoids profibrotic TGF-beta1 induction[J]. Invest Ophthalmol Vis Sci, 2009, 50(8):3688-3695.

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