Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

Abstract

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.

Ocular surface reconstruction using stem cell and tissue engineering

“…For that reason, continuous careful observation and direct examination will be needed to establish a proper understanding of limbal stem cell theory. The subject was well summarized and discussed in the excellent recent review (West et al, 2015).…”

Autologous Limbal Stem Cell Transplantation: The Progression of Diagnosis and Treatment

“…29 The first, the limbal epithelial stem cell hypothesis, was described in the introduction, and is the most widely accepted. The second model, known as the corneal epithelial stem cell (CESC) hypothesis, proposes that basal corneal epithelial cells dispersed throughout the corneal surface are responsible for normal cell maintenance, whereas LSC become involved only during times of acute cell loss.…”

Limbal epithelial stem cells in regeneration of corneal epithelium – clinical and molecular aspects

“…Rogówka jest zbudowana z pięciu warstw: nabłonka przedniego, blaszki granicznej przedniej, inaczej błony Bowmana, istoty właściwej (zrębu), blaszki granicznej tylnej, zwanej też błoną Decemeta, oraz nabłonka tylnego, zwanego inaczej śródbłonkiem [13]. Rogówka odgrywa rolę w załamaniu światła i jest odpowiedzialna za 2 / 3 mocy refrakcyjnej oka [15,16].…”

“…Białko to często w literaturze określane jako BCRP1, czyli białko pierwsze oporności raka piersi, może być odpowiedzialne za cechy odporności komórek macierzystych na uszkodzenia i działanie czynników toksycznych [23]; ABCG2 może również chronić LESC przed stresem oksydacyjnym przez transport małych niskocząsteczkowych białek odpowiedzialnych za procesy proliferacji, róż-nicowania i apoptozy [13]. Białka α9-, α6-, β1-integryny [23], cytokeratyna 15 (CK15), cytokeratyna 14 (CK14) [13] oraz receptor EGFR również używane są jako markery komórek progenitorowych rąbka rogów-ki [16]. Potwierdzono natomiast, że komórki warstwy epitelialnej rogówki wykazują ekspresję cytokeratyny 3 (CK3) oraz cytokeratyny 12 (CK12) [26,27,28,29].…”

“…Nie stwierdzono obecności tych białek w komórkach epitelialnych pochodzących z rąbka rogówki [23,30,31]. Co więcej, markerami negatywnymi dla rąbko-wych komórek macierzystych oprócz wymienionych cytokeratyn mogą być: nestyna, E-kadheryna, koneksyna 43 i inwolukryna [16,23]. Ponadto LESC wytwarzają enzymy metaboliczne, np.…”