• Corneal epithelium
• Eplerenone
• Limbal stem cells
• Mineralocorticoid receptor
• Spironolactone

• Animals
• Limbus Corneae/drug effects
• Limbus Corneae/pathology
• Limbus Corneae/metabolism
• Stem Cells/drug effects
• Stem Cells/pathology
• Stem Cells/metabolism
• Mineralocorticoid Receptor Antagonists/pharmacology
• Disease Models, Animal
• Rats
• Spironolactone/pharmacology
• Spironolactone/analogs & derivatives
• Male
• Eplerenone/pharmacology
• Epithelium, Corneal/drug effects
• Epithelium, Corneal/pathology
• Epithelium, Corneal/metabolism
• Corneal Diseases/drug therapy
• Corneal Diseases/pathology
• Corneal Diseases/metabolism
• Rats, Sprague-Dawley
• Rats, Transgenic
• Corneal Neovascularization/drug therapy
• Corneal Neovascularization/pathology
• Corneal Neovascularization/metabolism
• Cornea/drug effects
• Cornea/pathology
• Limbal Stem Cell Deficiency

• collagen cross-linking
• risk factors
• scar

• Humans
• Cross-Linking Reagents/therapeutic use
• Collagen/metabolism
• Riboflavin/therapeutic use
• Photosensitizing Agents/therapeutic use
• Ultraviolet Rays
• Cicatrix/etiology
• Cicatrix/diagnosis
• Keratoconus/drug therapy
• Keratoconus/metabolism
• Keratoconus/diagnosis
• Photochemotherapy/methods
• Epithelium, Corneal/pathology
• Epithelium, Corneal/metabolism
• Corneal Topography

• Limbal stem cell deficiency
• marginal keratitis
• ocular rosacea

• Humans
• Male
• Female
• Limbus Corneae/pathology
• Adult
• Middle Aged
• Aged
• Corneal Diseases/diagnosis
• Corneal Diseases/therapy
• Visual Acuity
• Adolescent
• Young Adult
• Child
• Stem Cells/pathology
• Retrospective Studies
• Child, Preschool
• Follow-Up Studies
• Glucocorticoids/therapeutic use
• Glucocorticoids/administration & dosage
• Limbal Stem Cell Deficiency

• biomaterials
• cornea
• limbal stem cell deficiency
• limbal stem cells
• scaffolds

• Humans
• Biocompatible Materials/chemistry
• Biocompatible Materials/pharmacology
• Stem Cells/cytology
• Stem Cells/metabolism
• Limbus Corneae/cytology
• Animals
• Regeneration/drug effects
• Tissue Scaffolds/chemistry
• Corneal Diseases/therapy
• Corneal Diseases/drug therapy
• Tissue Engineering/methods
• Cornea/cytology
• Cornea/metabolism
• Stem Cell Transplantation
• Limbal Stem Cell Deficiency

• VR200025 U.S. Department of Defense
• 20/59A University of NSW Animal Care and Ethics Committee
• 23/27B University of NSW Animal Care and Ethics Committee
• HC16338 University of NSW Human Research Ethics Committee
• HC200703 SMILE lenticules

• Cell therapy
• Cornea
• Endothelial cells
• Extracellular matrix
• Limbal stem cells
• Microenvironment
• Stroma
• Transplantation

• Humans
• Corneal Diseases/therapy
• Stem Cell Transplantation/methods
• Cell- and Tissue-Based Therapy/methods
• Cellular Microenvironment/physiology
• Cornea
• Corneal Transplantation/methods

• contact lens
• cornea
• ocular surface
• rehabilitation
• treatment surgery

• Humans
• Retrospective Studies
• Male
• Female
• Middle Aged
• Visual Acuity/physiology
• Adult
• Mouth Mucosa/transplantation
• Aged
• Contact Lenses
• Limbus Corneae/cytology
• Corneal Diseases/surgery
• Corneal Diseases/physiopathology
• Stevens-Johnson Syndrome/surgery
• Stevens-Johnson Syndrome/physiopathology
• Pemphigoid, Benign Mucous Membrane/surgery
• Pemphigoid, Benign Mucous Membrane/physiopathology
• Follow-Up Studies
• Cells, Cultured
• Cell Transplantation/methods
• Treatment Outcome

• Japanese Ministry of Education, Culture, Sports, Science and Technology
• Japan Agency for Medical Research and Development
• Japanese Ministry of Health, Labor, and Welfare

• Stevens-Johnson syndrome
• chemical burn
• keratolimbal allograft
• limbal stem cell deficiency
• mucous membrane pemphigoid
• thermal burn

• Minnesota Lions Vision Foundation

• Male
• Humans
• Young Adult
• Adult
• Photorefractive Keratectomy/methods
• Limbal Stem Cell Deficiency
• Lasers, Excimer/therapeutic use
• Cornea/surgery
• Myopia/surgery
• Refraction, Ocular

• LESC transplantation
• contact lens
• limbal epithelial stem cells
• limbal stem cell deficiency
• limbal stem cells

• Humans
• Young Adult
• Adult
• Retrospective Studies
• Cicatrix
• Transplantation, Autologous
• Limbus Corneae/surgery
• Corneal Injuries
• Contact Lenses
• Limbal Stem Cell Deficiency
• Burns, Chemical/surgery
• Stem Cell Transplantation
• Corneal Diseases/surgery

• Animals
• Rabbits
• Cornea/metabolism
• Contact Lenses/adverse effects
• Corneal Injuries
• Vitamins/pharmacology
• Vitamins/metabolism
• Dietary Supplements
• Nutrients
• Amino Acids/metabolism
• Water

• Contact lens
• Dropout
• Dry eye
• Environment
• Lifestyle choice
• Non-compliance
• Ocular health
• Ocular surgery
• Quality of life
• Systematic review

• Humans
• Quality of Life
• COVID-19/epidemiology
• Contact Lenses, Hydrophilic/adverse effects
• Dry Eye Syndromes/etiology
• Life Style

• Palisades of Vogt
• aniridia
• contact lens-induced LSCD
• dry eye syndrome
• limbal stem cell deficiency
• limbal stem cell transplantation
• limbal stem cells
• meibomian gland dysfunction
• ocular burn-induced LSCD
• xeroderma pigmentosum

• Humans
• Toxic Optic Neuropathy
• Corneal Diseases/chemically induced
• Corneal Diseases/therapy
• Cornea
• Contact Lenses
• Multiple Myeloma

• cornea
• ocular surface
• stem cells

• limbal epithelial stem cells
• ets1
• hmga2

Corneal stem/progenitor cells are typical adult stem/progenitor cells. The human cornea covers the front of the eyeball, which protects the eye from the outside environment while allowing vision. The location and function demand the cornea to maintain its transparency and to continuously renew its epithelial surface by replacing injured or aged cells through a rapid turnover process in which corneal stem/progenitor cells play an important role. Corneal stem/progenitor cells include mainly corneal epithelial stem cells, corneal endothelial cell progenitors and corneal stromal stem cells. Since the discovery of corneal epithelial stem cells (also known as limbal stem cells) in 1971, an increasing number of markers for corneal stem/progenitor cells have been proposed, but there is no consensus regarding the definitive markers for them. Therefore, the identification, isolation and cultivation of these cells remain challenging without a unified approach. In this review, we systematically introduce the profile of biological characterizations, such as anatomy, characteristics, isolation, cultivation and molecular markers, and clinical applications of the three categories of corneal stem/progenitor cells.

• Corneal epithelial stem cells
• Corneal endothelium stem cells
• Corneal stromal stem cells
• Bioengineering
• Gene markers

• limbal stem cell deficiency
• limbal stem cell therapy
• limbal stem cell transplantation
• limbal stem cells
• stem cell therapeutics

• Humans
• Limbus Corneae
• Corneal Diseases/therapy
• Cornea
• Stem Cells
• Homeostasis

• I01 BX004234 BLRD VA
• P30 EY001792 NEI NIH HHS
• R01 EY027912 NEI NIH HHS
• EY01792 NIH HHS

• Anti-Bacterial Agents/therapeutic use
• Contact Lenses, Hydrophilic
• Corneal Dystrophies, Hereditary/drug therapy
• Corneal Edema/diagnosis
• Corneal Edema/drug therapy
• Corneal Edema/etiology
• Corneal Injuries
• Humans
• Lubricant Eye Drops
• Male
• Middle Aged
• Prednisolone
• Tobramycin, Dexamethasone Drug Combination
• Vision Disorders

• K08 EY033859 NEI NIH HHS
• K12 EY031372 NEI NIH HHS

• ophthalmology
• optometry
• paediatric
• systemic disease

The corneal epithelium serves to protect the underlying cornea from the external environment and is essential for corneal transparency and optimal visual function. Regeneration of this epithelium is dependent on a population of stem cells residing in the basal layer of the limbus, the junction between the cornea and the sclera. The limbus provides the limbal epithelial stem cells (LESCs) with an optimal microenvironment, the limbal niche, which strictly regulates their proliferation and differentiation. Disturbances to the LESCs and/or their niche can lead to the pathologic condition known as limbal stem cell deficiency (LSCD) whereby the corneal epithelium is not generated effectively. This has deleterious effects on the corneal and visual function, due to impaired healing and secondary corneal opacification. In this concise review, we summarize the characteristics of LESCs and their niche, and present the current and future perspectives in the management of LSCD with an emphasis on restoring the function of the limbal niche.

• Cornea/pathology
• Corneal Diseases/pathology
• Corneal Diseases/therapy
• Epithelium, Corneal
• Humans
• Limbus Corneae
• Stem Cells

• NEI NIH HHS
• R01 EY024349 NEI NIH HHS
• National Eye Institute
• NIH

• Aniridia congénita
• Congenital aniridia
• Cultivo de células madre epiteliales
• Cultivo de células mesenquimales
• Keratopathy
• Keratoplasty
• Keratoprostheses
• Limbal stem cell culture
• Limbal stem cell transplantation
• Mesenchymal cell culture
• Queratopatía
• Queratoplastia
• Queratoprótesis
• Trasplante de células madre limbares

• Aniridia/genetics
• Cornea
• Corneal Diseases/surgery
• Corneal Transplantation
• Humans
• Quality of Life

• Extended soft contact lens wear
• In vivo confocal microscopy
• Limbal stem cell deficiency
• Limbal stem cells

The protective function and transparency provided by the corneal epithelium are dependent on and maintained by the regenerative capacity of limbal epithelial stem cells (LESCs). These LESCs are supported by the limbal niche, a specialized microenvironment consisting of cellular and non-cellular components. Disruption of the limbal niche, primarily from injuries or inflammatory processes, can negatively impact the regenerative ability of LESCs. Limbal stem cell deficiency (LSCD) directly hampers the regenerative ability of the corneal epithelium and allows the conjunctival epithelium to invade the cornea, which results in severe visual impairment. Treatment involves restoring the LESC population and functionality; however, few clinically practiced therapies currently exist. This review outlines the current understanding of the limbal niche, its pathology and the emerging approaches targeted at restoring the limbal niche. Most emerging approaches are in developmental phases but show promise for treating LSCD and accelerating corneal regeneration. Specifically, we examine cell-based therapies, bio-active extracellular matrices and soluble factor therapies in considerable depth.

• corneal epithelium
• limbal epithelial stem cells
• limbal stem cell niche
• mesenchymal stem cells
• ocular surface regeneration

• KL2 TR002002 NCATS NIH HHS
• EY024349 NEI NIH HHS

In the human cornea, regeneration of the epithelium is regulated by the stem cell reservoir of the limbus, which is the marginal region of the cornea representing the anatomical and functional border between the corneal and conjunctival epithelium. In support of this concept, extensive limbal damage, e.g., by chemical or thermal injury, inflammation, or surgery, may induce limbal stem cell deficiency (LSCD) leading to vascularization and opacification of the cornea and eventually vision loss. These acquired forms of limbal stem cell deficiency may occur uni- or bilaterally, which is important for the choice of treatment. Moreover, a variety of inherited diseases, such as congenital aniridia or dyskeratosis congenita, are characterized by LSCD typically occurring bilaterally. Several techniques of autologous and allogenic stem cell transplantation have been established. The limbus can be restored by transplantation of whole limbal grafts, small limbal biopsies or by ex vivo-expanded limbal cells. In this review, the physiology of the corneal epithelium, the pathophysiology of LSCD, and the therapeutic options will be presented.

• cornea
• epithelium
• graft
• limbus
• niche
• stem cell deficiency
• transplantation

Spectral-domain optical coherence tomography (SD-OCT) has been used to observe the morphology of the palisades of Vogt (POV) with satisfactory resolutions. In this study, we used SD-OCT to examine the microstructure of the POV in ocular surface disorders with limbal involvement. We detect subclinical limbal pathologies based on five parameters, including (1) decreased epithelial thickness, (2) loss of the sharp stromal tip, (3) loss of the smooth epithelial-stromal interface, (4) dilated stromal vessels, and (5) decreased POV density. Eighteen eyes of 10 patients with advancing wavelike epitheliopathy (AWE) and 15 eyes of 9 patients with phlyctenular keratitis/ocular rosacea were recruited. SD-OCT could detect abnormal changes in the POV in 100% of the lesion sites. In presumed-healthy areas of the diseased eyes diagnosed by slit-lamp biomicroscopy, SD-OCT detected abnormal changes in the POV in 100% of the eyes in both groups. In patients with unilateral disease, abnormal changes in the POV were detected by SD-OCT in 50% and 100% of presumed-healthy eyes diagnosed by slit-lamp biomicroscopy in the AWE group and phlyctenular keratitis/ocular rosacea group, respectively. SD-OCT is powerful in detecting POV changes in ocular surface disorders and can provide useful information that cannot be provided by slit-lamp biomicroscopy.

• Aphakia
• Bandage lens
• Irregular astigmatism
• Ocular surface disease
• Scleral lens
• Therapeutic contact lens

• Xenopus
• cornea epithelial stem cells
• disease models
• limbal stem cell deficiency
• lineage tracing and corneal wound healing

• Dry eye
• glaucoma
• ocular surface disease
• preservative-free eyedrops
• preservatives

• Universitätsklinikum Köln (8977)

Destruction of the limbus and depletion of limbal stem cells (LSCs), the adult progenitors of the corneal epithelium, leads to limbal stem cell deficiency (LSCD). LSCD is a rare, progressive ocular surface disorder which results in conjunctivalisation and neovascularisation of the corneal surface. Many strategies have been used in the treatment of LSCD, the common goal of which is to regenerate a self-renewing, transparent, and uniform epithelium on the corneal surface. The development of these techniques has frequently resulted from collaboration between stem cell translational scientists and ophthalmologists. Direct transplantation of autologous or allogeneic limbal tissue from a healthy donor eye is regarded by many as the technique of choice. Expansion of harvested LSCs in vitro allows smaller biopsies to be taken from the donor eye and is considered safer and more acceptable to patients. This technique may be utilised in unilateral cases (autologous) or bilateral cases (living related donor). Recently developed, simple limbal epithelial transplant (SLET) can be performed with equally small biopsies but does not require in vitro cell culture facilities. In the case of bilateral LSCD, where autologous limbal tissue is not available, autologous oral mucosa epithelium can be expanded in vitro and transplanted to the diseased eye. Data on long-term outcomes (over 5 years of follow-up) for many of these procedures is needed, and it remains unclear how they produce a self-renewing epithelium without recreating the vital stem cell niche. Bioengineering techniques offer the ability to re-create the physical characteristics of the stem cell niche, while induced pluripotent stem cells offer an unlimited supply of autologous LSCs. In vivo confocal microscopy and anterior segment OCT will complement impression cytology in the diagnosis, staging, and follow-up of LSCD. In this review we analyse recent advances in the pathology, diagnosis, and treatment of LSCD.

• Cornea
• Corneal limbus
• Corneal transplantation
• In vivo confocal microscopy
• Limbal niche
• Limbal stem cells
• Mesenchymal stem cell transplantation
• Oral mucosa stem cell transplantation
• Stem cell transplantation
• Tissue engineering

• Amniotic membrane
• HC-HA/PTX3
• Limbal stem cell deficiency
• Limbus
• Niche
• Stem cell

To describe the clinical features of Korean patients with contact lens-induced limbal stem cell deficiency (CL-LSCD).

Medical records of 22 patients who were diagnosed with CL-LSCD between 2014 and 2019 were reviewed retrospectively. Outcome measures included demographics, clinical presentation, treatment, clinical course, and pattern of contact lens (CL) wear.

Forty-two eyes of 22 patients were found to have typical changes associated with CL-LSCD. Twenty (91%) patients were women and mean age was 36 ± 12 years. All patients had myopia with mean spherical equivalent of −7.52 ± 3.2 diopter. Twenty (91%) patients had bilateral disease and the location of limbal involvement was diffuse in 20 eyes (47.6%) and partial in 22 eyes (52.4%, superior in 20 eyes and inferior in 2 eyes). Fourteen (63.6%) patients complained of decreased visual acuity. Average period of CL wear was 14 ± 9 years. Four patients used cosmetic colored CLs and four patients had a history of overnight CL wear. All 12 patients who completed follow-up (28 ± 42 weeks) showed improvement in visual acuity and ocular surface condition after cessation of CL wear and medical treatment. Of them, five (42%) patients showed full recovery while seven (58%) showed partial recovery.

If a patient with a history of CL wear for an extended period of time presents with decreased visual acuity, practitioners should perform detailed examinations with suspicion of CL-LSCD, including fluorescein staining. CL-LSCD is usually reversible and close follow-up with conservative treatment is recommended as the initial treatment option.

• Complications
• Hydrophilic contact lenses
• Limbal stem cell deficiency

• Anterior segment optical coherence tomography angiography
• Corneal neovascularization
• Limbal stem cell deficiency
• Limbal vasculature

• Contact lens
• Cornea
• Diabetes
• Epithelium
• Infectious keratitis

• Blood Glucose/analysis
• Contact Lenses/adverse effects
• Diabetes Mellitus/blood
• Diabetes Mellitus/physiopathology
• Diabetic Retinopathy/etiology
• Epithelium, Corneal/innervation
• Epithelium, Corneal/microbiology
• Epithelium, Corneal/physiopathology
• Glucose/analysis
• Humans
• Monitoring, Ambulatory/instrumentation
• Monitoring, Ambulatory/methods
• Patient Safety
• Risk Factors
• Tears/chemistry

• R01 EY024546 NEI NIH HHS
• R01 EY024333 NEI NIH HHS
• P30 EY030413 NEI NIH HHS
• P30 EY020799 NEI NIH HHS
• R01 EY029258 NEI NIH HHS

To present a novel non-parametric algorithm for detecting the position of the human eye limbus in three dimensions and a new dynamic method for measuring the full 360° visible iris boundary known as white-to-white distance along the eye horizontal line.

The study included 88 participants aged 23 to 65 years (37.7±9.7), 47 females and 41 males. Clinical characteristics, height data and the apex coordinates and 1024×1280 pixel digital images of the eyes were taken by an Eye Surface Profiler and processed by custom-built MATLAB codes. A dynamic light intensity frequency based white-to-white detection process and a novel three-dimensional method for limbus detection is presented.

Evidence of significant differences (p<0.001) between nasal-temporal and superior-inferior white-to-white distances in both right and left eyes were found (nasal-temporal direction; 11.74±0.42 mm in right eyes and 11.82±0.47 mm in left eyes & superior-inferior direction; 11.52±0.45 mm in right eyes and 11.55±0.46 mm in left eyes). Average limbus nasal-temporal diameters were 13.64±0.55 mm for right eyes, and 13.74±0.40 mm for left eyes, however the superior-inferior diameters were 13.65±0.54 mm, 13.75±0.38 mm for right and left eyes, respectively. No significant difference in limbus contours has been observed either between the nasal-temporal direction (p = 0.91) and the superior-inferior direction (p = 0.83) or between the right (p = 0.18) and left eyes (p = 0.16). Evidence of tilt towards the nasal-temporal side in the three-dimensional shape of the limbus was found. The right eyes mean limbus contour tilt around the X-axis was -0.3±1.35° however, their mean limbus contour tilt around the Y-axis was 1.76±0.9°. Likewise, the left eyes mean limbus contour tilt around the X-axis was 0.77±1.25° and the mean limbus contour tilt around the Y-axis was -1.54±0.89°.

The white-to-white distance in the human eye is significantly larger in the nasal-temporal direction than in the superior-inferior direction. The human limbus diameter was found not to vary significantly in these directions. The 3D measures show that the limbus contour does not lay in one plane and tends to be higher on the nasal-inferior side of the eye.

Identification and characterization of the limbal epithelial stem cells (LESCs) has proven to be a major accomplishment in anterior ocular surface biology. These cells have been shown to be a subpopulation of limbal epithelial basal cells, which serve as the progenitor population of the corneal epithelium. LESCs have been demonstrated to play an important role in maintaining corneal epithelium homeostasis. Many ocular surface diseases, including intrinsic (e.g., Sjogren's syndrome) or extrinsic (e.g., alkali or thermal burns) insults, which impair LESCs, can lead to limbal stem cell deficiency (LSCD). LSCD is characterized by an overgrowth of conjunctival-derived epithelial cells, corneal neovascularization, and chronic inflammation, eventually leading to blindness. Treatment of LSCD has been challenging, especially in bilateral total LSCD. Recently, advances in LESC research have led to novel therapeutic approaches for treating LSCD, such as transplantation of the cultured limbal epithelium. These novel therapeutic approaches have demonstrated efficacy for ocular surface reconstruction and restoration of vision in patients with LSCD. However, they all have their own limitations. Here, we describe the current status of LSCD treatment and discuss the advantages and disadvantages of the available therapeutic modalities.

• contact lenses
• ocular surface disease
• scleral lenses

• Anterior-segment optical coherence tomography
• Conjunctival marker
• Diagnosis
• Impression cytology
• In vivo confocal microscopy
• Limbal stem cell deficiency
• Molecular marker

• Corneal Diseases/diagnosis
• Epithelium, Corneal/pathology
• Humans
• Limbus Corneae/pathology
• Microscopy, Confocal
• Stem Cells/pathology

• P30 EY000331 NEI NIH HHS
• R01 EY021797 NEI NIH HHS