Corneal epithelial wound healing (original) (raw)
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Biological modulation of corneal epithelial wound healing
Arquivos Brasileiros de Oftalmologia
The transparency and maintenance of corneal epithelial integrity are essential for its optical properties and, to preserve these characteristics, the epithelium undergoes continuous renewal. This renewal depends on the control of cell proliferation and differentiation mediated by mitogenic factors responsible for increasing mitoses and stimulating cellular migration. Cell-cell communication plays a pivotal role in epithelial healing process, and several cytokines and growth factors are involved in this process. Understanding the cross-talk and paracrine effects of these cytokines and growth factors released can help in the search for new therapeutic strategies to treat ocular surface diseases.
Scientific Reports
Proper wound healing is dynamic in order to maintain the corneal integrity and transparency. Impaired or delayed corneal epithelial wound healing is one of the most frequently observed ocular defect and difficult to treat. Cyclin dependen kinase (cdk), a known cell cycle regulator, required for proper proliferating and migration of cell. We therefore investigated the role of cell cycle regulator cdk10, member of cdk family and its functional association with transcriptional factor (ETS2) at active phase of corneal epithelial cell migration. Our data showed that cdk10 was associated with ETS2, while its expression was upregulated at the active phase (18 hours) of cell migration and gradually decrease as the wound was completely closed. Topical treatment with anti-cdk10 and ETS2 antibodies delayed the wound closure time at higest concentration (10 µg/ml) compared to control. Further, our results also showed increased mRNA expression of cdk10 and ETS2 at active phase of migration at approximately 2 fold. Collectively, our data reveals that cdk10 and ETS2 efficiently involved during corneal wound healing. Further studies are warranted to better understand the mechanism and safety of topical cdk10 and ETS2 proteins in corneal epithelial wound-healing and its potential role for human disease treatment. Corneal epithelial injuries and burns produce extensive damage to the ocular surface epithelium and may cause significant loss of function 1. A rapid and efficient healing from injuries and environmental damges is necessary to maintain the cornea barrier that is essential for appropriate vision 2. Delayed in corneal epithelial wounds healing occur in number of disease states, however, persistence of these wounds can lead to loss of vision and even perforation of the eye 3. The World Health Organization (WHO) was estimatated 710 corneal ulcers per 100 000 population every year in south east asia region 4. However, in Pakistan corneal injuries or trauma are the common cause of blindness after cataract but data available about injuries is limited and does not indicate the magnitude of the problem. Recently Baig R et al. reported 39.7% eye injuries among all ocular complaints at emergency department (ED) visits in a private tertiary care hospital Karachi Pakistan 5. In our region, it was also reported that the frequency of trauma was 66% while metallic particles and road accedents were the major cause of ocular injuries 6,7. To reduce the potential of these debilitating injury or wounds is to promote the epithelial migration and decrease the chances of ocular infection with limited toxicity. Treatments for non-healing corneal wounds are limited and no specific therapy available so far. Knowing proper cell cycle division mechanism and specifically with their regulators would thus help to development a new therapeutic tools which trigger or control cell migration and proliferation. A fundamental requirement for proper proliferating and migration of cell, is the
Apoptosis in the initiation, modulation and termination of the corneal wound healing response
Experimental Eye Research, 2007
Stromal keratocyte apoptosis has been well-characterized as an early initiating event of the corneal wound healing response, triggering subsequent cellular processes that include bone marrow-derived cell infiltration, proliferation and migration of residual keratocyte cells, and, in some circumstances, generation of myofibroblast cells. Recent studies, however, have suggested a more general role for apoptosis in the overall stromal wound healing response that includes modulation and termination functions. This review article highlights, and ties together, recent studies that have demonstrated the important role apoptosis likely plays in the weeks to months following an initial insult to the cornea-depending on the type and extent of corneal injury.
Investigative Ophthalmology & Visual Science, 2008
PURPOSE. The reepithelialization of the corneal surface is an important process for restoring the imaging properties of this tissue. The purpose of the present study was to characterize and validate a new human in vitro three-dimensional corneal wound healing model by studying the expression of basement membrane components and integrin subunits that play important roles during epithelial cell migration and to verify whether the presence of exogenous factors could accelerate the reepithelialization. METHODS. Tissue-engineered human cornea was wounded with a 6-mm biopsy punch, and the reepithelialization from the surrounding margins was studied. Biopsy samples of the reepithelialized surface were harvested 3 days after wounding and were processed for histologic, electron microscopic, and immunofluorescence analyses. The effects of fibrin and epithelial growth factor (EGF) on wound reepithelialization were also studied. RESULTS. Results demonstrated that this in vitro model allowed the migration of human corneal epithelial cells on a natural extracellular matrix. During reepithelialization, epithelial cell migration followed a consistent wavelike pattern similar to that reported for human corneal wound healing in vivo. This model showed a histologic appearance similar to that of native tissue as well as expression and modulation of basement membrane components and the integrin subunits known to be main actors during the wound healing process. It also allowed quantification of the reepithelialization rate, which was significantly accelerated in the presence of fibrin or EGF. The results indicated that ␣ v  6 integrin expression was increased in the mi-grating epithelial cells compared with the surrounding corneal tissue. CONCLUSIONS. The similarity observed with the in vivo wound healing process supports the use of this tissue-engineered model for investigating the basic mechanisms involved in corneal reepithelialization. Moreover, this model may also be used as a tool to screen agents that affect reepithelialization or to evaluate the effect of growth factors before animal testing.
Wound healing of the corneal epithelium: a review
Asian Biomedicine
The corneal epithelium (CE) forms the outermost layer of the cornea. Despite its thickness of only 50 μm, the CE plays a key role as an initial barrier against any insults to the eye and contributes to the light refraction onto the retina required for clear vision. In the event of an injury, the cornea is equipped with many strategies contributing to competent wound healing, including angiogenic and immune privileges, and mechanotransduction. Various factors, including growth factors, keratin, cytokines, integrins, crystallins, basement membrane, and gap junction proteins are involved in CE wound healing and serve as markers in the healing process. Studies of CE wound healing are advancing rapidly in tandem with the rise of corneal bioengineering, which employs limbal epithelial stem cells as the primary source of cells utilizing various types of biomaterials as substrates.
Increased apoptosis and abnormal wound-healing responses in the heterozygous Pax6+/− mouse cornea
… ophthalmology & visual …, 2006
Corneal wound healing involves a cascade of interactions between the epithelium and stroma. Pax6 is upregulated, and early events include epithelial cell migration and apoptosis of superficial keratocytes. The mouse heterozygous Pax6 (Pax6 ϩ/Ϫ ) corneal phenotype mimics human aniridia-related keratopathy (ARK), and some aspects of wound healing have been shown to be abnormal, including matrix metalloproteinase (MMP)-9 expression. The purpose of this study was to test whether the Pax6 ϩ/Ϫ genotype affects corneal wound-healing responses, including stromal cell apoptosis, epithelial cell migration rate, and MMP secretion in culture. METHOD. Pax6 ϩ/Ϫ and wild-type (Pax6 ϩ/ϩ ) mice were killed and their corneas wounded by epithelial debridement. Whole eyes were cultured in organ culture and corneal epithelial healing rates and keratocyte apoptosis were quantified by topical fluorescein staining and TUNEL, respectively. Dissociated corneal epithelial cells from Pax6 ϩ/Ϫ and wild-type mice were cultured, and the activities of secreted MMP-9 were determined by zymography. RESULTS. Wound-healing rates during the first 6 hours were significantly faster for larger wounds and for Pax6 ϩ/Ϫ corneas. Compared with wild-type, wounded Pax6 ϩ/Ϫ eyes showed significantly more stromal cell apoptosis, and cultured Pax6 ϩ/Ϫ corneal epithelial cells produced lower MMP-9 activity. CONCLUSIONS. The cumulative effect of abnormal wound-healing responses, characterized by increased stromal cell apoptosis and reduced levels of MMP-9 secretion may contribute to the corneal changes in the Pax6 ϩ/Ϫ mice. Possible contribu-tions of elevated stromal cell apoptosis and other abnormal wound-healing responses to ARK are discussed. (Invest Ophthalmol Vis Sci.
Corneal Repair and Regeneration: Current Concepts and Future Directions
Frontiers in Bioengineering and Biotechnology, 2019
The cornea is a unique tissue and the most powerful focusing element of the eye, known as a window to the eye. Infectious or non-infectious diseases might cause severe visual impairments that need medical intervention to restore patients' vision. The most prominent characteristics of the cornea are its mechanical strength and transparency, which are indeed the most important criteria considerations when reconstructing the injured cornea. Corneal strength comes from about 200 collagen lamellae which criss-cross the cornea in different directions and comprise nearly 90% of the thickness of the cornea. Regarding corneal transparency, the specific characteristics of the cornea include its immune and angiogenic privilege besides its limbus zone. On the other hand, angiogenic privilege involves several active cascades in which anti-angiogenic factors are produced to compensate for the enhanced production of proangiogenic factors after wound healing. Limbus of the cornea forms a border between the corneal and conjunctival epithelium, and its limbal stem cells (LSCs) are essential in maintenance and repair of the adult cornea through its support of corneal epithelial tissue repair and regeneration. As a result, the main factors which threaten the corneal clarity are inflammatory reactions, neovascularization, and limbal deficiency. In fact, the influx of inflammatory cells causes scar formation and destruction of the limbus zone. Current studies about wound healing treatment focus on corneal characteristics such as the immune response, angiogenesis, and cell signaling. In this review, studied topics related to wound healing and new approaches in cornea regeneration, which are mostly related to the criteria mentioned above, will be discussed.
Control of cellular proliferation in the bovine cornea: An in vitro study
Eye, 1989
Keratocytes from the bovine cornea secrete a factor(s) that stimulates the prolifera tion of corneal epithelial cells. The novel finding of this study is that this stimulation was only achieved if the epithelial cells were already proliferating. Cells which had stopped growing could not be stimulated to re-enter the growth cycle. This stimu lation was not reciprocal; the growth of keratocytes was not stimulated by factor(s) secreted by the epithelium, whereas epithelial factors were able to stimulate the proliferation of thermocytes. The importance of these non-reciprocal growth responses to corneal wound heal ing and immune response is discussed.
Translational Research in Corneal Epithelial Wound Healing
Eye & Contact Lens: Science & Clinical Practice, 2010
To review both the roles of fibronectin and the sensory neurotransmitter substance P in corneal epithelial wound healing and the clinical application of these agents to treat persistent corneal epithelial defects. Results: Fibronectin is expressed at the site of corneal epithelial defects, serves as a provisional matrix for the migration of epithelial cells, and stimulates epithelial wound healing in vitro and in animal models. Eyedrops containing autologous plasma fibronectin are also effective for the treatment of persistent epithelial defects of the cornea in patients. Substance P and insulin-like growth factor-1 synergistically stimulate corneal epithelial wound healing in vitro and in animal models. Furthermore, the administration of eyedrops containing both a substance P-derived peptide (FGLM-amide) and insulin-like growth factor-1-derived peptide (SSSR) is effective for the treatment of persistent epithelial defects in individuals with neurotrophic keratopathy. Conclusions: Basic research on the mechanism of corneal epithelial wound healing has the potential to lead to the development of new modes of treatment for persistent corneal epithelial defects. Clinical experience with eyedrops containing fibronectin or both FGLM-amide and SSSR has highlighted the importance of the basement membrane and neural stimuli in maintenance of the integrity of the normal corneal epithelium.
Experimental Eye Research, 2001
After wounding, the corneal endothelium heals primarily by migration of adjacent cells into the denuded wound area. In this study, it has been attempted to identify elements of the intracellular signaling pathway activated through basic Fibroblast Growth Factor (FGF-2)-and Protein Kinase C (PKC)-modulated migration, using speci®c inhibitors and stimulators of second messengers in a cell culture model. Bovine corneal endothelial cells (BCEC) were grown to con¯uency and experiments performed with ®rst passage cells under serum-free conditions. A central circular`wound' was made with a specially designed trephine. In different experiments, cells were incubated with either FGF-2 (10 ng ml À1 ), pertussis toxin (PTX; 1±50 ng ml À1 ), phorbol 12-myristate 13-acetate (PMA; 50 ng ml À1 ), 2,4 H -di-bromoacetophenone (DAP; 5 mM), 1-(5-iosquinolinesulphonyl)-2-methyl-piperazine dihydrochloride (H7; 10 mM), indomethacin (5 ng ml À1 ), nordihydroguaiaretic acid (NDGA; 10 ng ml À1 ), 2-(4-morpholinyl)-8-pheny-4H-1-benzopyran-4-one (LY294002; 10 mM) or different combinations of these agents. Unsupplemented cultures served as controls. Migration was quantitated by counting the cells inside the denuded area in one randomly chosen section from the wound edge 72 hr after wounding. Cell toxicity was determined with the trypan blue exclusion test. Results were statistically analysed by Student's t-test. FGF-2 and PMA (a protein kinase C activator) both stimulated migration of endothelial cells at 2 . 2-and 3 . 1-fold, respectively. The PLA 2 inhibitor DAP and the PKC inhibitor H7 both signi®cantly reduced PMA-stimulated migration to control levels but had no effect (DAP) or even stimulated (H7) FGF-2-modulated migration. PTX did not affect FGF-2-stimulated migration. The phosphoinositol (3)-kinase inhibitor LY294002 signi®cantly reduced FGF-2-mediated stimulation of endothelial migration similar to the rate of control cultures. LY294002 had no effect when applied together with PMA. The cyclooxygenase inhibitor indomethacin did not in¯uence migration rates of the cells added either alone or in combination with PMA and FGF-2, respectively. The lipoxygenase inhibitor NDGA signi®cantly reduced the number of migrating cells in cultures with no other supplements, or of those supplemented with either PMA or FGF-2. FGF-2-induced endothelial migration in vitro is not dependent on PKC/PLA 2 or pertussis-toxin sensitive G-protein pathways but rather requires activation of a phosphoinositol (3)-kinase-like enzyme and/or arachidonic acid release with subsequent liberation of lipoxygenase products. Independent of FGF-2, PKC is a major intracellular effector of corneal endothelial migration activity after wounding and stimulates migration via the PLA 2dependent generation of lipoxygenase metabolites.