Corneal Goblet Cells and Their Niche: Implications for Corneal Stem Cell Deficiency

Pajoohesh‐Ganji, Ahdeah; Pal‐Ghosh, Sonali; Tadvalkar, Gauri; Stepp, Mary Ann

doi:10.1002/stem.1176

Cited by 53 publications

(59 citation statements)

References 43 publications

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“…Tgfbr2 conditional deletion in K14-expressing cells results in progressive periorbital tissue expansion with narrowing of the palpebral fissure Murine ocular surface epithelium is derived from K14-expressing cells (Pajoohesh-Ganji et al, 2012;Zhang et al, 2013). Mice that lack Tgfbr2 in stratified epithelia expressing K14 (cKO mice; K14-Cre×Tgfbr2 flox/flox ), including skin, oral and anogenital epithelia, are susceptible to squamous cell carcinoma formation (Lu et al, 2006;Guasch et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

et al. 2014

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The ocular surface epithelia, including the stratified but nonkeratinized corneal, limbal and conjunctival epithelium, in concert with the epidermal keratinized eyelid epithelium, function together to maintain eye health and vision. Abnormalities in cellular proliferation or differentiation in any of these surface epithelia are central in the pathogenesis of many ocular surface disorders. Goblet cells are important secretory cell components of various epithelia, including the conjunctiva; however, mechanisms that regulate goblet cell differentiation in the conjunctiva are not well understood. Herein, we report that conditional deletion of transforming growth factor β receptor II (Tgfbr2) in keratin 14-positive stratified epithelia causes ocular surface epithelial hyperplasia and conjunctival goblet cell expansion that invaginates into the subconjunctival stroma in the mouse eye. We found that, in the absence of an external phenotype, the ocular surface epithelium develops properly, but young mice displayed conjunctival goblet cell expansion, demonstrating that TGFβ signaling is required for normal restriction of goblet cells within the conjunctiva. We observed increased expression of SAM-pointed domain containing ETS transcription factor (SPDEF) in stratified conjunctival epithelial cells in Tgfbr2 cKO mice, suggesting that TGFβ restricted goblet cell differentiation directly by repressing Spdef transcription. Gain of function of Spdef in keratin 14-positive epithelia resulted in the ectopic formation of goblet cells in the eyelid and peripheral cornea in adult mice. We found that Smad3 bound two distinct sites on the Spdef promoter and that treatment of keratin 14-positive cells with TGFβ inhibited SPDEF activation, thereby identifying a novel mechanistic role for TGFβ in regulating goblet cell differentiation.

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Section: Resultsmentioning

confidence: 99%

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

et al. 2014

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“…While most adult stem cells are multipotent, generating multiple cell types, stem cells that maintain the corneal epithelium are generally presumed to be unipotent, only producing the corneal epithelial cells. Although one report shows that they may also produce the goblet cells that enter the corneal epithelium in response to large wounds [12] , we have not considered this possible additional role of the stem cells in this review.…”

Section: Alternative Hypotheses Of Corneal Epithelial Maintenancementioning

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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“…Furthermore, one study has proposed the existence of compound niches of cells that exist in the limbus of the mouse in unwounded corneas [133] . However, after wounding these compound niches were able to migrate onto the surface of the cornea and express corneal epithelial cytokeratins while also retaining both features of the compound niche and features of goblet cells.…”

Section: Ex Vivo Expansion Of Lscs On Amniotic Membranementioning

confidence: 99%

Limbal stem cells: Central concepts of corneal epithelial homeostasis

Yoon¹

2014

WJSC

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A strong cohort of evidence exists that supports the localisation of corneal stem cells at the limbus. The distinguishing characteristics of limbal cells as stem cells include slow cycling properties, high proliferative potential when required, clonogenicity, absence of differentiation marker expression coupled with positive expression of progenitor markers, multipotency, centripetal migration, requirement for a distinct niche environment and the ability of transplanted limbal cells to regenerate the entire corneal epithelium. The existence of limbal stem cells supports the prevailing theory of corneal homeostasis, known as the XYZ hypothesis where X represents proliferation and stratification of limbal basal cells, Y centripetal migration of basal cells and Z desquamation of superficial cells. To maintain the mass of cornea, the sum of X and Y must equal Z and very elegant cell tracking experiments provide strong evidence in support of this theory. However, several recent studies have suggested the existence of oligopotent stem cells capable of corneal maintenance outside of the limbus. This review presents a summary of data which led to the current concepts of corneal epithelial homeostasis and discusses areas of controversy surrounding the existence of a secondary stem cell reservoir on the corneal surface

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Corneal Goblet Cells and Their Niche: Implications for Corneal Stem Cell Deficiency

Cited by 53 publications

References 43 publications

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

TGFβ signaling inhibits goblet cell differentiation via SPDEF in conjunctival epithelium

Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

Limbal stem cells: Central concepts of corneal epithelial homeostasis

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