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Cell Stem Cell Jul 2021The accessibility and transparency of the cornea permit robust stem cell labeling and in vivo cell fate mapping. Limbal epithelial stem cells (LSCs) that renew the...
The accessibility and transparency of the cornea permit robust stem cell labeling and in vivo cell fate mapping. Limbal epithelial stem cells (LSCs) that renew the cornea are traditionally viewed as rare, slow-cycling cells that follow deterministic rules dictating their self-renewal or differentiation. Here, we combined single-cell RNA sequencing and advanced quantitative lineage tracing for in-depth analysis of the murine limbal epithelium. These analysis revealed the co-existence of two LSC populations localized in separate and well-defined sub-compartments, termed the "outer" and "inner" limbus. The primitive population of quiescent outer LSCs participates in wound healing and boundary formation, and these cells are regulated by T cells, which serve as a niche. In contrast, the inner peri-corneal limbus hosts active LSCs that maintain corneal epithelial homeostasis. Quantitative analyses suggest that LSC populations are abundant, following stochastic rules and neutral drift dynamics. Together these results demonstrate that discrete LSC populations mediate corneal homeostasis and regeneration.
Topics: Animals; Cornea; Homeostasis; Limbus Corneae; Mice; Stem Cells; Wound Healing
PubMed: 33984282
DOI: 10.1016/j.stem.2021.04.003 -
Proceedings of the National Academy of... Jan 2023Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is...
Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise "adaptive regeneration." We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.
Topics: Mice; Animals; Limbus Corneae; Cell Differentiation; Cornea; Epithelium, Corneal; Wound Healing; Dry Eye Syndromes; Homeostasis
PubMed: 36595669
DOI: 10.1073/pnas.2204134120 -
Experimental Eye Research Apr 2021The function of limbal stem/progenitor cells (LSCs) is critical to maintain corneal epithelial homeostasis. Many external insults and intrinsic defects can be... (Review)
Review
The function of limbal stem/progenitor cells (LSCs) is critical to maintain corneal epithelial homeostasis. Many external insults and intrinsic defects can be deleterious to LSCs and their niche microenvironment, resulting in limbal stem cell dysfunction or deficiency (LSCD). Ocular comorbidities, frequent in eyes with LSCD, can exacerbate the dysfunction of residual LSCs, and limit the survival of transplanted LSCs. Clinical presentation and disease evolution vary among different etiologies of LSCD. New ocular imaging modalities and molecular markers are now available to standardize the diagnosis criteria and stage the severity of the disease. Medical therapies may be sufficient to reverse the disease if residual LSCs are present. A stepwise approach should be followed to optimize the ocular surface, eliminate the causative factors and treat comorbid conditions, before considering surgical interventions. Furthermore, surgical options are selected depending on the severity and laterality of the disease. The standardized diagnostic criteria to stage the disease is necessary to objectively evaluate and compare the efficacy of the emerging customized therapies.
Topics: Corneal Diseases; Epithelium, Corneal; Humans; Limbus Corneae; Stem Cells
PubMed: 33571530
DOI: 10.1016/j.exer.2021.108437 -
Clinical & Experimental Optometry Sep 2017This review surveys available literature for corneal and limbal dimensions. With modern scleral lenses, these measures have become central to determining the overall... (Review)
Review
This review surveys available literature for corneal and limbal dimensions. With modern scleral lenses, these measures have become central to determining the overall size of a lens for satisfactory fitting. In general, published values are not based on a definition of what is being measured. In addition, the most widely accepted average corneal diameter measurement, 11.7 × 10.6 mm, emanates from one source published more than 50 years ago. This value was not based on a measurement but appears to be the cumulative impression of measurements from seven studies conducted between 67 and 127 years ago. Furthermore, in most instances, if at all stated, quoted measures are based on horizontal visible iris diameter, providing limited acknowledgement of limbal width and its inclusion as part of the corneal diameter. The corneo-scleral sulcus from one side to the other has been measured, giving a larger diameter, but may include at least part of the limbus. More objective measurements are possible with modern ophthalmic instrumentation but the lack of structural definition and low magnification resolution with these techniques raises concerns with the accuracy of the results. Measurement of the horizontal visible iris diameter does not include the limbal width, which means that the horizontal visible iris diameter is an underestimate of the true corneo-limbal diameter. This review concludes that the width of the limbus has been neither structurally defined nor accurately measured and that there is a need for the development of new protocols for determining the dimensions of the average cornea and limbus. It is predicted that more accurate measures will indicate that to vault across cornea with limbus and provide excellent comfort, the average cornea will need a lens to have a diameter of 16.0 mm or larger.
Topics: Contact Lenses; Humans; Iris; Limbus Corneae; Prosthesis Fitting; Vision Disorders
PubMed: 28868754
DOI: 10.1111/cxo.12583 -
Stem Cell Reports Dec 2023Recently, the murine cornea has reemerged as a robust stem cell (SC) model, allowing individual SC tracing in living animals. The cornea has pioneered seminal... (Review)
Review
Recently, the murine cornea has reemerged as a robust stem cell (SC) model, allowing individual SC tracing in living animals. The cornea has pioneered seminal discoveries in SC biology and regenerative medicine, from the first corneal transplantation in 1905 to the identification of limbal SCs and their transplantation to successfully restore vision in the early 1990s. Recent experiments have exposed unexpected properties attributed to SCs and progenitors and revealed flexibility in the differentiation program and a key role for the SC niche. Here, we discuss the limbal SC model and its broader relevance to other tissues, disease, and therapy.
Topics: Mice; Animals; Epithelium, Corneal; Limbus Corneae; Cornea; Stem Cells; Cell Differentiation; Stem Cell Transplantation
PubMed: 38039972
DOI: 10.1016/j.stemcr.2023.10.023 -
Current Opinion in Ophthalmology Mar 2020Most microinvasive glaucoma surgery (MIGS) procedures bypass outflow resistance residing proximally in the trabecular meshwork and inner wall of Schlemm's canal. A novel... (Review)
Review
PURPOSE OF REVIEW
Most microinvasive glaucoma surgery (MIGS) procedures bypass outflow resistance residing proximally in the trabecular meshwork and inner wall of Schlemm's canal. A novel procedure combining trabeculotomy with viscodilation adds to this by also addressing distal resistance of the canal and collector channel ostia. This review examines the development and evidence for both trabeculotomy and canaloplasty separately and the combination in a single procedure.
RECENT FINDINGS
Recent aqueous angiography studies have confirmed the segmental nature of outflow through Schlemm's canal highlighting the need to address distal outflow pathway resistance. Combined trabeculotomy and viscodilation ab interno is a novel approach with a new purpose-designed device (OMNI Surgical System) becoming available to surgeons in early 2018. Recent results as both a standalone and combined with cataract procedure demonstrate significant intraocular pressure reductions with an average 41% reduction from baseline in the pseudophakic group.
SUMMARY
Targeting both distal as well as proximal points of outflow resistance in the conventional pathway may prove to be a highly efficacious MIGS modality. Additional large prospective studies are currently ongoing to confirm these preliminary results.
Topics: Aqueous Humor; Glaucoma, Open-Angle; History, 20th Century; History, 21st Century; Humans; Intraocular Pressure; Limbus Corneae; Trabecular Meshwork; Trabeculectomy
PubMed: 31904595
DOI: 10.1097/ICU.0000000000000639 -
Experimental Eye Research May 2017Integrins are a family of heterodimeric transmembrane receptors that mediate adhesion to the extracellular matrix (ECM). In addition to their role as adhesion receptors,... (Review)
Review
Integrins are a family of heterodimeric transmembrane receptors that mediate adhesion to the extracellular matrix (ECM). In addition to their role as adhesion receptors, integrins can act as ''bidirectional signal transducers'' that coordinate a large number of cellular activities in response to the extracellular environment and intracellular signaling events. This bidirectional signaling helps maintain tissue homeostasis. Dysregulated bidirectional signaling, however, could trigger the propagation of feedback loops that can lead to the establishment of a disease state such as glaucoma. Here we discuss the role of integrins and bidirectional signaling as they relate to the glaucomatous phenotype with special emphasis on the αvβ3 integrin. We present evidence that this particular integrin may have a significant impact on the pathogenesis of glaucoma.
Topics: Animals; Extracellular Matrix; Glaucoma; Humans; Integrin alphaVbeta3; Integrins; Limbus Corneae; Optic Disk; Signal Transduction; Trabecular Meshwork
PubMed: 27185161
DOI: 10.1016/j.exer.2016.05.011 -
Asia-Pacific Journal of Ophthalmology... Dec 2020Treatment of limbal stem cell deficiency is challenging. Multiple options can be adopted according to the underlying cause and the patient and physician preferences.... (Review)
Review
Treatment of limbal stem cell deficiency is challenging. Multiple options can be adopted according to the underlying cause and the patient and physician preferences. Stem cell transplant is a common treatment modality and several techniques have been described with outcomes varying by the laterality of the condition. Keratoprosthesis is a preferred option for bilateral conditions. Indications for type 1 and type 2 keratoprosthesis differ and the past 2 decades have seen a revolution in the field of keratoprosthesis with encouraging and improved outcomes. Management also includes preventive measures and measures to optimize/stabilize the ocular surface that would go a long way in reducing the deterioration of the ocular surface. The aim of this review is to provide an overview of the currently available techniques and to present a comprehensive algorithm to assist in decision making for unilateral and bilateral limbal stem cell deficiency.
Topics: Corneal Diseases; Humans; Limbus Corneae; Stem Cell Transplantation; Visual Acuity
PubMed: 33323706
DOI: 10.1097/APO.0000000000000326 -
The Ocular Surface Apr 2019The epithelial cell layer that covers the surface of the cornea provides a protective barrier while maintaining corneal transparency. The rapid and effective turnover of... (Review)
Review
The epithelial cell layer that covers the surface of the cornea provides a protective barrier while maintaining corneal transparency. The rapid and effective turnover of these epithelial cells depends, in part, on the limbal epithelial stem cells (LESCs) located in a specialized microenvironment known as the limbal niche. Many disorders affecting the regeneration of the corneal epithelium are related to deficiency and/or dysfunction of LESCs and the limbal niche. Current approaches for regenerating the corneal epithelium following significant injuries such as burns and inflammatory attacks are primarily aimed at repopulating the LESCs. This review summarizes and assesses the clinical feasibility and efficacy of current and emerging approaches for reconstruction of the limbal niche. In particular, the application of mesenchymal stem cells along with appropriate biological scaffolds appear to be promising strategies for long-term revitalization of the limbal niche.
Topics: Cell Count; Corneal Diseases; Epithelium, Corneal; Humans; Limbus Corneae; Stem Cell Niche; Stem Cell Transplantation
PubMed: 30633966
DOI: 10.1016/j.jtos.2019.01.002 -
Current Opinion in Ophthalmology Jul 2017The aim of this review is to describe the underlying mechanisms of corneal epithelial homeostasis in addition to illustrating the vital role of the limbal epithelial... (Review)
Review
PURPOSE OF REVIEW
The aim of this review is to describe the underlying mechanisms of corneal epithelial homeostasis in addition to illustrating the vital role of the limbal epithelial stem cells (LESCs) and the limbal niche in epithelial regeneration and wound healing.
RECENT FINDINGS
The shedded corneal epithelial cells are constantly replenished by the LESCs which give rise to epithelial cells that proliferate, differentiate, and migrate centripetally. While some recent studies have proposed that epithelial stem cells may also be present in the central cornea, the predominant location for the stem cells is the limbus. The limbal niche is the specialized microenvironment consisting of cells, extracellular matrix, and signaling molecules that are essential for the function of LESCs. Disturbances to limbal niche can result in LESC dysfunction; therefore, limbal stem cell deficiency should also be considered a limbal niche deficiency. Current and in-development therapeutic strategies are aimed at restoring the limbal niche, by medical and/or surgical treatments, administration of trophic factors, and cell based therapies.
SUMMARY
The corneal epithelium is constantly replenished by LESCs that are housed within the limbal niche. The limbal niche is the primary determinant of the LESC function and novel therapeutic approaches should be focused on regeneration of this microenvironment.
Topics: Cell Differentiation; Cell Proliferation; Corneal Diseases; Epithelial Cells; Epithelium, Corneal; Homeostasis; Humans; Limbus Corneae; Stem Cells; Wound Healing
PubMed: 28399066
DOI: 10.1097/ICU.0000000000000378