Regenerative Cell Therapy for Corneal Endothelium

Bartáková, Alena; Kunzevitzky, Noelia J.; Goldberg, Jeffrey L

doi:10.1007/s40135-014-0043-7

Cited by 29 publications

(30 citation statements)

References 99 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For this reason, there has become a need for tissue-engineered substitutes that can overcome this scarcity. For this reason, the establishment of an efficient cultivation technique for functional CECs is an essential and inevitable part for the tissue engineering of endothelium [24].…”

Section: Discussionmentioning

confidence: 99%

LY2109761, Transforming Growth Factor β Receptor Type I and Type II Dual Inhibitor, is a Novel Approach to Suppress Endothelial Mesenchymal Transformation in Human Corneal Endothelial Cells

Zhang¹,

Miao²,

Ke³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Preventing undesirable endothelial-mesenchymal transformation (EnMT) with repetitious in vitro expansion of human corneal endothelial cells (CECs) is a pivotal issue in cornea regeneration. Previous studies have shown that inhibition of the TGF-β pathway reduces epithelial-mesenchymal transformation. However, its potential role in EnMT remains poorly understood. As such, the effect of LY2109761, a novel TGF-β receptor type I and type II dual inhibitor, was investigated on EnMT. Methods: CECs cultured with various concentrations of LY2109761 were evaluated for their growth rate and phenotype. Additionally, the expression of functional markers (sodium-potassium pump Na⁺/K⁺-ATPase and the tight junction protein ZO-1) and mesenchymal markers (CD73, fibronectin, and vimentin) was detected using immunostaining and western blot. The mRNA expressions were also assayed by real-time polymerase chain reaction analysis. Results: At a 1 μM concentration, LY2109761 did not influence the proliferation of CECs and subsequent experiments were therefore performed using this concentration. Furthermore, CECs cultured in the presence of 1 μM LY2109761 maintained their ability to grow as a monolayer of hexagonal-shaped cells. The expression of functional markers increased in LY2109761-treated CECs, while the expression of mesenchymal markers decreased (both in protein and mRNA levels). Conclusion: Inhibition of TGF-β receptor type I and type II by LY2109761 maintained the phenotype of CECs and inhibited the EnMT process. These results indicate the possible continuous in vitro expansion of CECs with normal function.

show abstract

Section: Discussionmentioning

confidence: 99%

LY2109761, Transforming Growth Factor β Receptor Type I and Type II Dual Inhibitor, is a Novel Approach to Suppress Endothelial Mesenchymal Transformation in Human Corneal Endothelial Cells

Zhang¹,

Miao²,

Ke³

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Corneal endothelial stem cells, unlike those in the epithelium or stroma, have not been definitively identified. However, the endothelial periphery contains cells with increased proliferative capacity, and it was suggested that this region could harbor endothelial stem cells (Winkelhart et al, 2005; Bartakova et al, 2014). Such cells, if identified, could eventually become a new therapeutic tool for wound healing and endothelial regeneration (Bartakova et al, 2014).…”

Section: Corneal Endothelial Wound Healingmentioning

confidence: 99%

“…However, the endothelial periphery contains cells with increased proliferative capacity, and it was suggested that this region could harbor endothelial stem cells (Winkelhart et al, 2005; Bartakova et al, 2014). Such cells, if identified, could eventually become a new therapeutic tool for wound healing and endothelial regeneration (Bartakova et al, 2014). Alternatively, some mesenchymal stem cells, e.g., from umbilical cord blood, could be potentially used for this purpose.…”

Section: Corneal Endothelial Wound Healingmentioning

confidence: 99%

Progress in corneal wound healing

Ljubimov

Saghizadeh

2015

Progress in Retinal and Eye Research

612

554

View full text Add to dashboard Cite

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 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.

show abstract

“…What differentiates these 2 techniques is the method of Advanced Therapy Medicinal Product delivery; either by intracameral injection of a cell suspension or by surgical transplantation of a tissue-engineered graft similar to conventional techniques. 10,67 Currently, a first cohort of patients is being treated using the cell suspension technique (UMIN000012534) by the Kinoshita group, whereas the scaffold-based Advanced Therapy Medicinal Product is limited to preclinical experiments. 45,48,51,63,69,91,108…”

Section: Advanced Therapy Medicinal Productsmentioning

confidence: 99%

A review of the evidence for in vivo corneal endothelial regeneration

Bogerd

Dhubhghaill

Koppen

et al. 2018

Survey of Ophthalmology

107

104

View full text Add to dashboard Cite

Human corneal endothelium has long been thought to be a nonmitotic cell layer with no endogenous reparative potential. Pathologies that damage endothelial function result in corneal decompensation and, if untreated, blindness. The mainstay of treatment involves partial or complete corneal replacement, amounting to 40% of all corneal transplants performed worldwide. We summarize the case reports describing complications postoperatively in the form of (sub)total graft detachment and those resulting in postoperative bare stroma. Complications during cataract and glaucoma surgeries leading to an uncovered posterior cornea are also included. We discuss the newer treatment strategies that are alternatives for current Descemet membrane endothelial keratoplasty and Descemet stripping automated endothelial keratoplasty, including partial grafts and stripping of the diseased cell layer. In more than half of the cases reviewed, corneal transparency returned despite incomplete or no corneal endothelial cell transplantation. We question the existing paradigm concerning corneal endothelial wound healing in vivo. The data support further clinical study to determine the safety of simple descemethorexis in central endothelial pathologies, such as Fuchs endothelial corneal dystrophy, where presence of healthy peripheral cells may allow successful corneal recompensation without the need for donor cells.

show abstract

Regenerative Cell Therapy for Corneal Endothelium

Cited by 29 publications

References 99 publications

LY2109761, Transforming Growth Factor β Receptor Type I and Type II Dual Inhibitor, is a Novel Approach to Suppress Endothelial Mesenchymal Transformation in Human Corneal Endothelial Cells

LY2109761, Transforming Growth Factor β Receptor Type I and Type II Dual Inhibitor, is a Novel Approach to Suppress Endothelial Mesenchymal Transformation in Human Corneal Endothelial Cells

Progress in corneal wound healing

A review of the evidence for in vivo corneal endothelial regeneration

Contact Info

Product

Resources

About