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Progress in Retinal and Eye Research May 2021The cornea is exquisitely designed to protect the eye while transmitting and focusing incoming light. Precise control of corneal hydration by the endothelial cell layer... (Review)
Review
The cornea is exquisitely designed to protect the eye while transmitting and focusing incoming light. Precise control of corneal hydration by the endothelial cell layer that lines the inner surface of the cornea is required for optimal transparency, and endothelial dysfunction or damage can result in corneal edema and visual impairment. Advances in corneal transplantation now allow selective replacement of dysfunctional corneal endothelium, providing rapid visual rehabilitation. A series of technique improvements have minimized complications and various adaptations allow use even in eyes with complicated anatomy. While selective endothelial keratoplasty sets a very high standard for safety and efficacy, a shortage of donor corneas in many parts of the world restricts access, prompting a search for alternatives. Clinical trials are underway to evaluate the potential for self-recovery after removal of dysfunctional central endothelium in patients with healthy peripheral endothelium. Various approaches to using cultured human corneal endothelial cells are also in clinical trials; these aim to multiply cells from a single donor cornea for use in potentially hundreds of patients. Pre-clinical studies are underway with induced pluripotent stem cells, endothelial stem cell regeneration, gene therapy, anti-sense oligonucleotides, and various biologic/pharmacologic approaches designed to treat, prevent, or retard corneal endothelial dysfunction. The availability of more therapeutic options will hopefully expand access around the world while also allowing treatment to be more precisely tailored to each individual patient.
Topics: Cornea; Corneal Transplantation; Descemet Stripping Endothelial Keratoplasty; Endothelial Cells; Endothelium, Corneal; Humans
PubMed: 32977001
DOI: 10.1016/j.preteyeres.2020.100904 -
Progress in Retinal and Eye Research Mar 2022The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are... (Review)
Review
The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are increasing the number of corneal transplants, thereby causing a global deficit of donor corneas and leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate the corneal endothelium offer a solution to the current tissue scarcity and a treatment to those in need. Methods for generating corneal endothelial cells into numbers that could address the current tissue shortage and the possible strategies used to deliver them have now become a therapeutic reality with clinical trials taking place in Japan, Singapore and Mexico. Nevertheless, there is still a long way before such therapies are approved by regulatory bodies and become clinical practice. Moreover, acellular corneal endothelial graft equivalents and certain drugs could provide a treatment option for specific disease conditions without the need of donor tissue or cells. Finally, with the emergence of gene modulation therapies to treat corneal endothelial disease, it would be possible to treat presymptomatic patients or those presenting early symptoms, drastically reducing the need for donor tissue. It is necessary to understand the most recent developments in this rapidly evolving field to know which conditions could be treated with which approach. This article provides an overview of the current and developing regenerative medicine therapies to treat corneal endothelial disease and provides the necessary guidance and understanding towards the treatment of corneal endothelial disease.
Topics: Corneal Diseases; Corneal Transplantation; Endothelial Cells; Endothelium, Corneal; Humans; Regenerative Medicine; Reproducibility of Results; Tissue Engineering
PubMed: 34237411
DOI: 10.1016/j.preteyeres.2021.100987 -
Indian Journal of Ophthalmology Mar 2021Specular microscopy is a noninvasive diagnostic tool that allows for in vivo evaluation of corneal endothelium in health and various diseased states. Endothelial imaging... (Review)
Review
Specular microscopy is a noninvasive diagnostic tool that allows for in vivo evaluation of corneal endothelium in health and various diseased states. Endothelial imaging helps in the diagnosis and management of several endothelial disorders. The review focuses on the principles of specular microscopy, limitations of endothelial imaging, and its interpretation in common conditions seen in the clinical practice. A thorough PubMed search was done using the keywords specular microscopy, corneal endothelium, and endothelial imaging.
Topics: Cell Count; Cornea; Endothelium, Corneal; Humans; Microscopy
PubMed: 33595465
DOI: 10.4103/ijo.IJO_574_20 -
Experimental Eye Research Nov 2016The posterior face of the cornea consists of the corneal endothelium, a monolayer of cuboidal cells that secrete and attach to Descemet's membrane, an exaggerated... (Review)
Review
The posterior face of the cornea consists of the corneal endothelium, a monolayer of cuboidal cells that secrete and attach to Descemet's membrane, an exaggerated basement membrane. Dysfunction of the endothelium compromises the barrier and pump functions of this layer that maintain corneal deturgesence. A large number of corneal endothelial dystrophies feature irregularities in Descemet's membrane, suggesting that cells create and respond to the biophysical signals offered by their underlying matrix. This review provides an overview of the bidirectional relationship between Descemet's membrane and the corneal endothelium. Several experimental methods have characterized a richly topographic and compliant biophysical microenvironment presented by the posterior surface of Descemet's membrane, as well as the ultrastructure and composition of the membrane as it builds during a lifetime. We highlight the signaling pathways involved in the mechanotransduction of biophysical cues that influence cell behavior. We present the specific example of Fuchs' corneal endothelial dystrophy as a condition in which a dysregulated Descemet's membrane may influence the progression of disease. Finally, we discuss some disease models and regenerative strategies that may facilitate improved treatments for corneal dystrophies.
Topics: Corneal Topography; Descemet Membrane; Endothelium, Corneal; Fuchs' Endothelial Dystrophy; Humans; Mechanotransduction, Cellular
PubMed: 27639516
DOI: 10.1016/j.exer.2016.09.004 -
The British Journal of Ophthalmology Apr 2021Corneal endothelial diseases are leading indications for corneal transplantations. With significant advancement in medical science and surgical techniques, corneal... (Review)
Review
Corneal endothelial diseases are leading indications for corneal transplantations. With significant advancement in medical science and surgical techniques, corneal transplant surgeries are now increasingly effective at restoring vision in patients with corneal diseases. In the last 15 years, the introduction of endothelial keratoplasty (EK) procedures, where diseased corneal endothelium (CE) are selectively replaced, has significantly transformed the field of corneal transplantation. Compared to traditional penetrating keratoplasty, EK procedures, namely Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), offer faster visual recovery, lower immunological rejection rates, and improved graft survival. Although these modern techniques can achieve high success, there are fundamental impediments to conventional transplantations. A lack of suitable donor corneas worldwide restricts the number of transplants that can be performed. Other barriers include the need for specialized expertise, high cost, and risks of graft rejection or failure. Research is underway to develop alternative treatments for corneal endothelial diseases, which are less dependent on the availability of allogeneic tissues - regenerative medicine and cell-based therapies. In this review, an overview of past and present transplantation procedures used to treat corneal endothelial diseases are described. Potential novel therapies that may be translated into clinical practice will also be presented.
Topics: Corneal Diseases; Descemet Stripping Endothelial Keratoplasty; Endothelium, Corneal; Graft Survival; Humans; Tissue Donors; Visual Acuity
PubMed: 32709756
DOI: 10.1136/bjophthalmol-2020-316149 -
Acta Ophthalmologica Nov 2014This study aims to systemically review the effect of laser iridotomy on the corneal endothelium. Searches were performed for studies that either compared corneal... (Review)
Review
This study aims to systemically review the effect of laser iridotomy on the corneal endothelium. Searches were performed for studies that either compared corneal endothelial cell density/count, corneal thickness and morphology pre- and postiridotomy, or evaluated the postiridotomy development of corneal decompensation. There were 26 eligible studies. Our review shows that the effect of laser iridotomy on the corneal endothelium has been investigated with varying results. Although it has been demonstrated to be a relatively safe procedure, there is still the potential long-term risk of corneal decompensation, for which a corneal transplantation may be indicated eventually. The longest interval between laser iridotomy and corneal decompensation reported was 8 years. Mechanisms proposed for endothelial damage include direct focal injury, thermal damage, mechanical shock waves, iris pigment dispersion, transient rise in intraocular pressure, inflammation, turbulent aqueous flow, time-dependent shear stress on endothelium, chronic breakdown of blood-aqueous barrier and damage from bubbles that settled onto the endothelium. Inherent risk factors identified were iridotrabecular contact, current or prior acute angle closure, pigmented irides, small iris-to-endothelium distance, pre-existing endothelial disease and diabetes. Intervention-related risk factors include laser type, delivery and quantity. The significance of the risk factors and their direct association with the development of corneal decompensation remain to be determined. Understanding these risk factors may allow physicians to counsel their patients better. They may offer opportunities for preventive strategies, allowing us to ensure that a procedure performed to prevent disease progression and visual loss does not cause further morbidity.
Topics: Humans; Cell Count; Corneal Edema; Endothelium, Corneal; Iridectomy; Iris; Laser Therapy; Risk Factors
PubMed: 24528451
DOI: 10.1111/aos.12367 -
Stem Cell Research & Therapy Oct 2021The corneal endothelium plays a key role in maintaining corneal transparency. Its dysfunction is currently treated with penetrating or lamellar keratoplasty. Advanced... (Review)
Review
The corneal endothelium plays a key role in maintaining corneal transparency. Its dysfunction is currently treated with penetrating or lamellar keratoplasty. Advanced cell therapy methods seek to address the persistent global deficiency of donor corneas by enabling the renewal of the endothelial monolayer with tissue-engineered grafts. This review provides an overview of recently published literature on the preparation of endothelial grafts for transplantation derived from cadaveric corneas that have developed over the last decade (2010-2021). Factors such as the most suitable donor parameters, culture substrates and media, endothelial graft storage conditions, and transplantation methods are discussed. Despite efforts to utilize alternative cellular sources, such as induced pluripotent cells, cadaveric corneas appear to be the best source of cells for graft preparation to date. However, native endothelial cells have a limited natural proliferative capacity, and they often undergo rapid phenotype changes in ex vivo culture. This is the main reason why no culture protocol for a clinical-grade endothelial graft prepared from cadaveric corneas has been standardized so far. Currently, the most established ex vivo culture protocol involves the peel-and-digest method of cell isolation and cell culture by the dual media method, including the repeated alternation of high and low mitogenic conditions. Culture media are enriched by additional substances, such as signaling pathway (Rho-associated protein kinase, TGF-β, etc.) inhibitors, to stimulate proliferation and inhibit unwanted morphological changes, particularly the endothelial-to-mesenchymal transition. To date, this promising approach has led to the development of endothelial grafts for the first in-human clinical trial in Japan. In addition to the lack of a standard culture protocol, endothelial-specific markers are still missing to confirm the endothelial phenotype in a graft ready for clinical use. Because the corneal endothelium appears to comprise phenotypically heterogeneous populations of cells, the genomic and proteomic expression of recently proposed endothelial-specific markers, such as Cadherin-2, CD166, or SLC4A11, must be confirmed by additional studies. The preparation of endothelial grafts is still challenging today, but advances in tissue engineering and surgery over the past decade hold promise for the successful treatment of endothelial dysfunctions in more patients worldwide.
Topics: Anion Transport Proteins; Antiporters; Cornea; Corneal Transplantation; Endothelial Cells; Endothelium, Corneal; Humans; Proteomics
PubMed: 34717745
DOI: 10.1186/s13287-021-02611-3 -
International Journal of Molecular... Apr 2021The cornea, while appearing to be simple tissue, is actually an extremely complex structure. In order for it to retain its biomechanical and optical properties, perfect... (Review)
Review
The cornea, while appearing to be simple tissue, is actually an extremely complex structure. In order for it to retain its biomechanical and optical properties, perfect organization of its cells is essential. Proper regeneration is especially important after injuries and in the course of various diseases. Eph receptors and ephrin are mainly responsible for the proper organization of tissues as well as cell migration and communication. In this review, we present the current state of knowledge on the role of Eph and ephrins in corneal physiology and diseases, in particular, we focused on the functions of the epithelium and endothelium. Since the role of Eph and ephrins in the angiogenesis process has been well established, we also analyzed their influence on conditions with corneal neovascularization.
Topics: Animals; Cornea; Corneal Diseases; Corneal Neovascularization; Endothelium, Corneal; Ephrins; Epithelium, Corneal; Humans; Molecular Targeted Therapy; Receptors, Eph Family
PubMed: 33925443
DOI: 10.3390/ijms22094567 -
Seminars in Ophthalmology 2019Fuchs endothelial corneal dystrophy (FECD) is characterized by the progressive degeneration of the corneal endothelium (CE). The purpose of this article is to review the... (Review)
Review
Fuchs endothelial corneal dystrophy (FECD) is characterized by the progressive degeneration of the corneal endothelium (CE). The purpose of this article is to review the diagnostic tools available to image and assess the CE in FECD. Slit-lamp biomicroscopy with specular reflection and retroillumination are important techniques to assess the CE. Objective diagnostic tests, such as retroillumination photographic analysis, specular microscopy, confocal microscopy (IVCM), and anterior segment optical coherence tomography, are valuable tools to evaluate the CE in FECD. Specular microscopy can be performed rapidly without touching the eye but requires a clear cornea with a smooth CE. In contrast, IVCM can image all layers of the cornea, even in advanced FECD. However, IVCM is contact-based and more technically challenging. It is important to select the appropriate objective diagnostic test to image and assess the CE in managing patients with FECD.
Topics: Diagnostic Techniques, Ophthalmological; Endothelium, Corneal; Fuchs' Endothelial Dystrophy; Humans; Microscopy, Confocal; Slit Lamp Microscopy; Tomography, Optical Coherence
PubMed: 31215821
DOI: 10.1080/08820538.2019.1632355 -
Investigative Ophthalmology & Visual... Dec 2019To establish Myh11 as a marker of a subset of corneal endothelial cells (CECs), and to demonstrate the feasibility of restoring the corneal endothelium with...
PURPOSE
To establish Myh11 as a marker of a subset of corneal endothelial cells (CECs), and to demonstrate the feasibility of restoring the corneal endothelium with Myh11-lineage (Myh11-Lin[+]) adipose-derived stromal cells (ASCs).
METHODS
Intraperitoneal administration of tamoxifen and (Z)-4-hydroxytamoxifen eyedrops were used to trace the lineage of Myh11-expressing cells with the Myh11-Cre-ERT2-flox-tdTomato mouse model. Immunostaining and Western blot characterized marker expression and spatial distribution of Myh11-Lin(+) cells in the cornea, and administration of 5-ethynyl-2'-deoxyuridine labeled proliferating cells. ASCs were isolated from epididymal adipose Myh11+ mural cells and treated with cornea differentiation media to evaluate corneal endothelial differentiation potential. Differentiated ASCs were injected into the anterior chamber to test for incorporation into corneal endothelium following scratch injury.
RESULTS
A subset of CECs express Myh11, a marker previously thought restricted to only mural cells. Myh11-Lin(+) CECs marked a stable subpopulation of cells in the cornea endothelium. Myh11-Lin(+) ASCs undergo CEC differentiation in vitro and incorporate into injured corneal endothelium.
CONCLUSIONS
Dystrophy and dysfunction of the corneal endothelium accounts for almost half of all corneal transplants, the maintenance of the cornea endothelium is poorly understood, and there are a lack of mouse models to study specific CEC populations. We establish a mouse model that can trace the cell fate of a subpopulation of CECs based on Myh11 expression. A subset of ASCs that share this Myh11 transcriptional lineage are capable of differentiating into CECs that can incorporate into injured corneal endothelium, revealing a potential cell source for creating engineered transplant material.
Topics: Adipocytes; Animals; Cell Count; Cell Differentiation; Cells, Cultured; Corneal Dystrophies, Hereditary; Corneal Transplantation; Disease Models, Animal; Endothelium, Corneal; Immunoblotting; Immunohistochemistry; Mice; Myosin Heavy Chains; Stromal Cells
PubMed: 31826231
DOI: 10.1167/iovs.19-27276