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      Concise Review: Stem Cells for Corneal Wound Healing

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          Abstract

          Corneal wound healing is a complex process that occurs in response to various injuries and commonly used refractive surgery. It is a significant clinical problem, which may lead to serious complications due to either incomplete (epithelial) or excessive (stromal) healing. Epithelial stem cells clearly play a role in this process, whereas the contribution of stromal and endothelial progenitors is less well studied. The available evidence on stem cell participation in corneal wound healing is reviewed, together with the data on the use of corneal and non‐corneal stem cells to facilitate this process in diseased or postsurgical conditions. Important aspects of corneal stem cell generation from alternative cell sources, including pluripotent stem cells, for possible transplantation upon corneal injuries or in disease conditions are also presented. S tem C ells 2017;35:2105–2114

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          Most cited references87

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          Progress in corneal wound healing.

          Corneal wound healing is a complex process involving cell death, migration, proliferation, differentiation, and extracellular matrix remodeling. Many similarities are observed in the healing processes of corneal epithelial, stromal and endothelial cells, as well as cell-specific differences. Corneal epithelial healing largely depends on limbal stem cells and remodeling of the basement membrane. During stromal healing, keratocytes get transformed to motile and contractile myofibroblasts largely due to activation of transforming growth factor-β (TGF-β) system. Endothelial cells heal mostly by migration and spreading, with cell proliferation playing a secondary role. In the last decade, many aspects of wound healing process in different parts of the cornea have been elucidated, and some new therapeutic approaches have emerged. The concept of limbal stem cells received rigorous experimental corroboration, with new markers uncovered and new treatment options including gene and microRNA therapy tested in experimental systems. Transplantation of limbal stem cell-enriched cultures for efficient re-epithelialization in stem cell deficiency and corneal injuries has become reality in clinical setting. Mediators and course of events during stromal healing have been detailed, and new treatment regimens including gene (decorin) and stem cell therapy for excessive healing have been designed. This is a very important advance given the popularity of various refractive surgeries entailing stromal wound healing. Successful surgical ways of replacing the diseased endothelium have been clinically tested, and new approaches to accelerate endothelial healing and suppress endothelial-mesenchymal transformation have been proposed including Rho kinase (ROCK) inhibitor eye drops and gene therapy to activate TGF-β inhibitor SMAD7. Promising new technologies with potential for corneal wound healing manipulation including microRNA, induced pluripotent stem cells to generate corneal epithelium, and nanocarriers for corneal drug delivery are discussed. Attention is also paid to problems in wound healing understanding and treatment, such as lack of specific epithelial stem cell markers, reliable identification of stem cells, efficient prevention of haze and stromal scar formation, lack of data on wound regulating microRNAs in keratocytes and endothelial cells, as well as virtual lack of targeted systems for drug and gene delivery to select corneal cells.
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            Role of the pericorneal papillary structure in renewal of corneal epithelium.

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              Chemical injuries of the eye: current concepts in pathophysiology and therapy.

              M Wagoner (2015)
              Chemical injuries of the eye may produce extensive damage to the ocular surface epithelium, cornea, and anterior segment, resulting in permanent unilateral or bilateral visual impairment. Pathophysiological events which may influence the final visual prognosis and which are amenable to therapeutic modulation include 1) ocular surface injury, repair, and differentiation, 2) corneal stromal matrix injury, repair and/or ulceration, and 3) corneal and stromal inflammation. Immediately following chemical injury, it is important to estimate and clinically grade the severity of limbal stem cell injury (by assessing the degree of limbal, conjunctival, and scleral ischemia and necrosis) and intraocular penetration of the noxious agent (by assessing clarity of the corneal stroma and anterior segment abnormalities). Immediate therapy is directed toward prompt irrigation and removal of any remaining reservoir of chemical contact with the eye. Initial medical therapy is directed promoting re-epithelialization and transdifferentiation of the ocular surface, augmenting corneal repair by supporting keratocyte collagen production and minimizing ulceration related to collagenase activity, and controlling inflammation. Early surgical therapy if indicated, is directed toward removal of necrotic corneal epithelium and conjunctiva, prompt re-establishment of an adequate limbal vascularity, and re-establishment of limbal stem cell population early in the clinical course, if sufficient evidence exists of complete limbal stem cell loss. Re-establishment of limbal stem cells by limbal autograft or allograft transplantation, or by transfer in conjunction with large diameter penetrating keratoplasty, may facilitate development of an intact, phenotypically correct corneal epithelium. Limbal stem cell transplantation may prevent the development of fibrovascular pannus or sterile corneal corneal ulceration, simplify visual rehabilitation, and improve the visual prognosis. Advances in ocular surface transplantation techniques which allow late attempts at visual rehabilitation of a scarred and vascularized cornea include limbal stem cell transplantation for incomplete transdifferentiation and persistent corneal epithelial dysfunction, and conjunctival and/or mucosal membrane transplantation for ocular surface mechanical dysfunction. Rehabilitation of the ocular surface may be followed, if necessary, by standard penetrating keratoplasty if all aspects of ocular surface rehabilitation are complete, or by large diameter penetrating keratoplasty if successful limbal stem cell transplantation cannot be achieved but other ocular surface rehabilitation is complete.
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                Author and article information

                Contributors
                Ljubimov@csmc.edu
                Journal
                Stem Cells
                Stem Cells
                10.1002/(ISSN)1549-4918
                STEM
                Stem Cells (Dayton, Ohio)
                John Wiley and Sons Inc. (Hoboken )
                1066-5099
                1549-4918
                26 July 2017
                October 2017
                : 35
                : 10 ( doiID: 10.1002/stem.v35.10 )
                : 2105-2114
                Affiliations
                [ 1 ] Cedars‐Sinai Medical Center, Regenerative Medicine Institute Los Angeles California USA
                [ 2 ] David Geffen School of Medicine at UCLA Los Angeles California USA
                Author notes
                [*] [* ]Correspondence: Alexander V. Ljubimov, Ph.D., D.Sc., FARVO, Cedars‐Sinai Medical Center, Regenerative Medicine Institute, 8700 Beverly Boulevard AHSP, A‐8319, Los Angeles, California 90048, USA. Telephone: 310‐248‐8583; Fax: 310‐248‐8066; e‐mail: Ljubimov@ 123456csmc.edu
                Author information
                http://orcid.org/0000-0003-2398-5319
                Article
                STEM2667
                10.1002/stem.2667
                5637932
                28748596
                37a0618e-7831-4692-b5c0-d68cdc31fbd9
                © 2017 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 09 March 2017
                : 16 June 2017
                : 02 July 2017
                Page count
                Figures: 5, Tables: 0, Pages: 10, Words: 7829
                Funding
                Funded by: NIH
                Award ID: R01 EY13431
                Award ID: R01 EY023429
                Award ID: R01 EY025377
                Funded by: Board of Governors Regenerative Medicine Institute
                Funded by: National Eye Institute
                Categories
                Tissue‐Specific Stem Cells
                Adipose Stem Cells/VSF
                Embryonic Stem Cells
                Induced Pluripotent stem cells
                Limbal Epithelial /Corneal Stem Cells
                Mesenchymal Stem Cells
                Lineage Specific Differentiation
                Stem Cell Niche
                Vision Loss / Repair
                Wound Healing / Fibrosis
                Tissue‐Specific Stem Cells
                Tissue‐Specific Stem Cells
                Custom metadata
                2.0
                stem2667
                October 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.1 mode:remove_FC converted:12.10.2017

                Molecular medicine
                corneal epithelium,keratocyte,corneal endothelium,wound healing,gene therapy,stem cell,pluripotent stem cell,cell transplantation

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