Cytokeratin 15 Can Be Used to Identify the Limbal Phenotype in Normal and Diseased Ocular Surfaces

Yoshida, Shigeo; Shimmura, Shigeto; Kawakita, Tetsuya; Miyashita, Hideyuki; Den, Seika; Shimazaki, Jun; Tsubota, Kazuo

doi:10.1167/iovs.06-0574

Cited by 152 publications

(131 citation statements)

References 35 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…During development, the periderm layer plays an important role in preventing pathological cell adhesions between the epithelial linings of adjacent organs, thus ensuring normal tissue formation. Our IHC examinations confirmed that the limbal stem cell marker K15 was exclusively expressed by the basal epithelial cells and that K13 marked the surface and suprabasal epithelium, as reported previously (Ramirez-Miranda et al, 2011;Yoshida et al, 2006). Also, the entire epithelium of MC-2, including the loose surface layers, expressed K13 and the periderm markers K17 and K19 (Fig.…”

Section: A Periderm Lining In Developing MC Structuressupporting

confidence: 90%

Generating minicorneal organoids from human induced pluripotent stem cells

et al. 2017

View full text Add to dashboard Cite

Corneal epithelial stem cells residing within the annular limbal crypts regulate adult tissue homeostasis. Autologous limbal grafts and tissue engineered corneal epithelial cell sheets have been widely used in the treatment of various ocular surface defects. In case of bilateral limbal defects, pluripotent stem cell (PSC) derived corneal epithelial cells are now being explored as an alternative to allogeneic limbal grafts. We report here an efficient method to generate complex three dimensional corneal organoids from human PSCs. The eye field primordial (EFP) clusters that emerged from differentiating PSCs developed into whole eye ball-like, self-organized, three dimensional, miniature structures consisting of retinal primordia (RP), corneal primordia (CP), primitive eye lid-like outer covering and ciliary margin zone-like adnexal tissues in a step-wise maturation process within 15 weeks. These minicorneal organoids recapitulate the early developmental events in vitro and displayed similar anatomical features and marker expression profiles as that of adult corneal tissues and offers an alternative tissue source for regenerating different layers of the cornea and eliminates the need for complicated cell enrichment procedures.

show abstract

Section: A Periderm Lining In Developing MC Structuressupporting

confidence: 90%

Generating minicorneal organoids from human induced pluripotent stem cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…In contrast, loss of FIH-1 promotes keratinocyte differentiation. Confirming these in vitro findings: (i) an increase in expression of Hes 1 and Hey 2, markers of Notch activity (3,13); (ii) a decrease in expression of p63 and K15, markers of undifferentiated limbal keratinocytes (14,15); and (iii) an increase in PAI-2, a marker of keratinocyte differentiation (16), were observed in the limbal epithelium of mice null for FIH-1. We identify an endogenous mechanism for keratinocytes to regulate FIH-1 levels via micro-RNA-31 (miR-31).…”

mentioning

confidence: 68%

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

Han¹,

Kaplan²,

Hamanaka

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

119

View full text Add to dashboard Cite

Notch plays a critical role in the transition from proliferation to differentiation in the epidermis and corneal epithelium. Furthermore, aberrant Notch signaling is a feature of diseases like psoriasis, eczema, nonmelanoma skin cancer, and melanoma where differentiation and proliferation are impaired. Whereas much is known about the downstream events following Notch signaling, factors responsible for negatively regulating Notch receptor signaling after ligand activation are incompletely understood. Notch can undergo hydroxylation by factor-inhibiting hypoxia-inducible factor 1 (FIH-1); however, the biological significance of this phenomenon is unclear. Here we show that FIH-1 expression is upregulated in diseased epidermis and corneal epithelium. Elevating FIH-1 levels in primary human epidermal keratinocytes (HEKs) and human corneal epithelial keratinocytes (HCEKs) impairs differentiation in submerged cultures and in a "three-dimensional" organotypic raft model of human epidermis, in part, via a coordinate decrease in Notch signaling. Knockdown of FIH-1 enhances keratinocyte differentiation. Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium, resulting in a more differentiated phenotype. microRNA-31 (miR-31) is an endogenous negative regulator of FIH-1 expression that results in keratinocyte differentiation, mediated by Notch activation. Ectopically expressing miR-31 in an undifferentiated corneal epithelial cell line promotes differentiation and recapitulates a corneal epithelium in a three-dimensional raft culture model. Our results define a previously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part, controlled through a miR-31/FIH-1 nexus.

show abstract

“…Interestingly, these nodules were strongly positive for keratin 14 (K14; Fig. 8F), however, the expression of keratin 15 (K15), which is normally detected in the conjunctival and limbal epithelium (Yoshida et al, 2006), was aberrantly extended into the central corneal epithelium upon expression of E3-catenin (Fig. 8G,H).…”

Section: E3-catenin-upregulated Expression Of Mmp-7 Downregulated Ementioning

confidence: 99%

Aberrant expression of a β-catenin gain-of-function mutant induces hyperplastic transformation in the mouse cornea

Zhang

Call

Yeh

et al. 2010

Journal of Cell Science

View full text Add to dashboard Cite

Summary-catenin signaling has been shown to play a fundamental role in embryonic development and tumorigenesis. In this study, we investigated the role of -catenin (Ctnnb1) in corneal homeostasis and tumorigenesis. Conditional expression of a murine Ctnnb1 gain-of-function mutation alone caused corneal neoplasia and neovascularization, resembling human ocular surface squamous neoplasia (OSSN). These corneas displayed an upregulation of cell proliferative markers (PCNA and p63), while presenting downregulation of both the Pax-6 transcription factor and the corneal differentiation marker cytokeratin 12. In addition, the expression of limbal-type keratin 15 ectopically extended to cornea, but the pattern of conjunctival keratin 4 and epidermal keratin 10 were unchanged. Moreover, epithelial E-cadherin and laminins decreased concomitantly with elevated levels of MMP-7. We also noticed a dramatic upregulation of pro-angiogenic factors (Vegf-A, Vegfr1) and angiopoietins in these corneas. Interestingly, all human OSSN specimens examined revealed nuclear -catenin immunoreactivity. Taken together, these results argue that -catenin activation is a crucial step during OSSN pathogenesis. Thus, inhibition of -catenin might be beneficial for treating this disease.

show abstract

Cytokeratin 15 Can Be Used to Identify the Limbal Phenotype in Normal and Diseased Ocular Surfaces

Abstract: Although the expression of K15 and K19 differ in humans and mice, specific staining patterns can be used to characterize the epithelial phenotype in normal and diseased ocular surface.

Cited by 152 publications

References 35 publications

Generating minicorneal organoids from human induced pluripotent stem cells

Generating minicorneal organoids from human induced pluripotent stem cells

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

Aberrant expression of a β-catenin gain-of-function mutant induces hyperplastic transformation in the mouse cornea

Contact Info

Product

Resources

About