Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics

Kulkarni, Bina; Tighe, Patrick J.; Mohammed, Imran; Yeung, Aaron M.; Powe, Desmond G.; Hopkinson, Andrew; Shanmuganathan, Vijay; Dua, Harminder S

doi:10.1186/1471-2164-11-526

Cited by 77 publications

(76 citation statements)

References 79 publications

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“…Epithelial SCs seem to be activated in case of massive epithelial damage, whereas physiological turnover is thought to be provided by TACs [32,33]. While the existence of epithelial SCs in the limbus is an old premise, the anatomic description of their specific niches is more recent [30,34]. These LECs are located at the ends of the palisades of Vogt, which are solid radial cords of cells in the extreme periphery of the corneal epithelium.…”

Section: Discussionmentioning

confidence: 99%

Revisited Microanatomy of the Corneal Endothelial Periphery: New Evidence for Continuous Centripetal Migration of Endothelial Cells in Humans

et al. 2012

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The control of corneal transparency depends on the integrity of its endothelial monolayer, which is considered nonregenerative in adult humans. In pathological situations, endothelial cell (EC) loss, not offset by mitosis, can lead to irreversible corneal edema and blindness. However, the hypothesis of a slow, clinically insufficient regeneration starting from the corneal periphery remains debatable. The authors have re-evaluated the microanatomy of the endothelium in order to identify structures likely to support this homeostasis model. Whole endothelia of 88 human corneas (not stored, and stored in organ culture) with mean donor age of 80 6 12 years were analyzed using an original flatmounting technique. In 61% of corneas, cells located at the extreme periphery (last 200 lm of the endothelium) were organized in small clusters with two to three cell layers around Hassall-Henle bodies. In 68% of corneas, peripheral ECs formed centripetal rows 830 6 295 lm long, with Descemet membrane furrows visible by scanning electron microscopy. EC density was significantly higher in zones with cell rows. When immunostained, ECs in the extreme periphery exhibited lesser differentiation (ZO-1, Actin, Na/ K ATPase, CoxIV) than ECs in the center of the cornea but preferentially expressed stem cell markers (Nestin, Telomerase, and occasionally breast cancer resistance protein) and, in rare cases, the proliferation marker Ki67. Stored corneas had fewer cell clusters but more Ki67-positive ECs. We identified a novel anatomic organization in the periphery of the human corneal endothelium, suggesting a continuous slow centripetal migration, throughout life, of ECs from specific niches.

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Section: Discussionmentioning

confidence: 99%

Revisited Microanatomy of the Corneal Endothelial Periphery: New Evidence for Continuous Centripetal Migration of Endothelial Cells in Humans

et al. 2012

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“…One type of crypt is formed by the regions of limbal epithelium between the upward-projecting stroma of the limbal palisades and these have been named "limbal crypts" (LCs) [8,9] . The other type of crypt (named "limbal epithelial crypts"; LECs) are more sparsely distributed (only 6-7 per eye) and are formed from epithelial projections from the periphery of the limbal palisades, which extend either radially from the limbus into the conjunctival stroma or circumferentially within the limbus (perpendicular to the palisades) [10,11] .…”

Section: The Corneal and Limbal Epitheliamentioning

confidence: 99%

Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

West¹,

Dora²,

Collinson

2015

WJSC

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In this review we evaluate evidence for three different hypotheses that explain how the corneal epithelium is maintained. The limbal epithelial stem cell (LESC) hypothesis is most widely accepted. This proposes that stem cells in the basal layer of the limbal epithelium, at the periphery of the cornea, maintain themselves and also produce transient (or transit) amplifying cells (TACs). TACs then move centripetally to the centre of the cornea in the basal layer of the corneal epithelium and also replenish cells in the overlying suprabasal layers. The LESCs maintain the corneal epithelium during normal homeostasis and become more active to repair significant wounds. Second, the corneal epithelial stem cell (CESC) hypothesis postulates that, during normal homeostasis, stem cells distributed throughout the basal corneal epithelium, maintain the tissue. According to this hypothesis, LESCs are present in the limbus but are only active during wound healing. We also consider a third possibility, that the corneal epithelium is maintained during normal homeostasis by proliferation of basal corneal epithelial cells without any input from stem cells. After reviewing the published evidence, we conclude that the LESC and CESC hypotheses are consistent with more of the evidence than the third hypothesis, so we do not consider this further. The LESC and CESC hypotheses each have difficulty accounting for one main type of evidence so we evaluate the two key lines of evidence that discriminate between them. Finally, we discuss how lineage-tracing experiments have begun to resolve the debate in favour of the LESC hypothesis. Nevertheless, it also seems likely that some basal corneal epithelial cells can act as long-term progenitors if limbal stem cell function is compromised. Thus, this aspect of the CESC hypothesis may have a lasting impact on our understanding of corneal epithelial maintenance, even if it is eventually shown that stem cells are restricted to the limbus as proposed by the LESC hypothesis.

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“…53 The surface of the human eye is covered by corneal epithelial cells, which regenerate from a small population of limbal epithelial stem cells (LESCs) found in limbal epithelial crypts at the peripheral cornea. 54 The human LAMA1 gene encodes an important basal membrane protein which is highly expressed in LESCs. 55 Interestingly, loss of the functional zebrafish homologue lama1 in ocular tissues leads to focal corneal dysplasia in adult zebrafish.…”

Section: Corneal Dystrophiesmentioning

confidence: 99%

The zebrafish eye—a paradigm for investigating human ocular genetics

Richardson¹,

Tracey‐White²,

Webster

et al. 2016

Eye

147

162

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Although human epidemiological and genetic studies are essential to elucidate the aetiology of normal and aberrant ocular development, animal models have provided us with an understanding of the pathogenesis of multiple developmental ocular malformations. Zebrafish eye development displays in depth molecular complexity and stringent spatiotemporal regulation that incorporates developmental contributions of the surface ectoderm, neuroectoderm and head mesenchyme, similar to that seen in humans. For this reason, and due to its genetic tractability, external fertilisation, and early optical clarity, the zebrafish has become an invaluable vertebrate system to investigate human ocular development and disease. Recently, zebrafish have been at the leading edge of preclinical therapy development, with their amenability to genetic manipulation facilitating the generation of robust ocular disease models required for large-scale genetic and drug screening programmes. This review presents an overview of human and zebrafish ocular development, genetic methodologies employed for zebrafish mutagenesis, relevant models of ocular disease, and finally therapeutic approaches, which may have translational leads in the future.

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Comparative transcriptional profiling of the limbal epithelial crypt demonstrates its putative stem cell niche characteristics

Cited by 77 publications

References 79 publications

Revisited Microanatomy of the Corneal Endothelial Periphery: New Evidence for Continuous Centripetal Migration of Endothelial Cells in Humans

Revisited Microanatomy of the Corneal Endothelial Periphery: New Evidence for Continuous Centripetal Migration of Endothelial Cells in Humans

Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

The zebrafish eye—a paradigm for investigating human ocular genetics

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