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.2013 Apr;35(2):289-300.
doi: 10.1007/s11357-011-9359-5. Epub 2012 Jan 15.

The impact of age on the physical and cellular properties of the human limbal stem cell niche

Affiliations

The impact of age on the physical and cellular properties of the human limbal stem cell niche

M Notara et al. Age (Dordr).2013 Apr.

Abstract

The limbal niche in the corneoscleral junction of the eye, habitat of the limbal epithelial stem cells (LESC), facilitates corneal epithelial regeneration by providing physical support and chemical signalling. Anatomical structures within the limbus, namely, limbal epithelial crypts and focal stromal projections, are believed to function as a putative niche for LESCs. In this study, the impact of age on the topography of this niche was investigated. Also, the relationship between niche topography and limbal epithelial cell phenotype was assessed. Ex vivo imaging of the limbus in cadaveric tissue of donors aged from infancy to 90 years was carried out using electron and confocal microscopy. The data suggested that the area occupied by the crypts was sharply reduced after the age of 60 years. The niche microstructures also became smoother with donor age. The phenotypic assessment of cultured limbal epithelial cells harvested from donors of different ages showed that the levels of putative stem cell markers as well as telomerase activity and telomere length remained unchanged, regardless of niche topography. However, the colony forming efficiency of the cultures was significantly reduced with age (p < 0.05). This is the first comprehensive study of the effect of age on the structural and phenotypic characteristics of the human limbal niche. The results have a significant biological value as they suggest a correlation of limbal architecture with decline of re-epithelialisation rate in older patients. Overall, the data also suggest that LESCs harvested from younger donors may be more suitable for cultured LESC therapy production.

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Figures

Fig. 1
Fig. 1
Schematic description of the methods used in the study for the quantification of the physical extent of the limbal niche features. The pictured SEM microphotograph montage is separated by thegreen lines in four quadrants, namely, superior, inferior, nasal and temporal. The surface area of the niche features is bordered by thered line and was calculated using image J. The degrees of arc (also measured by image J) are defined by the beginning and the end of the LECs and FSPs as well as the geometrical centre of the cornea (yellow angle,θ)
Fig. 2
Fig. 2
Confocal microscopy montages of limbal rim wholemounts harvested froma a 48-year-old donor andb a 70-year-old donor.c High-power image depicting a LEC (red arrows) surrounded by a blood vessel (yellow arrows). FSPs are noted withgreen arrows
Fig. 3
Fig. 3
Percentage of niche surface area and degrees of arc ina,c superior andb,d inferior quadrants, respectively, in different age groups (*p < 0.05, **p < 0.001)
Fig. 4
Fig. 4
Percentage of niche surface area and degrees of arc ina,c nasal andb,d temporal quadrants, respectively, in different age groups (**p < 0.001)
Fig. 5
Fig. 5
Percentage ofa total niche surface area andb total degrees of arc compared to the total cornea in different age groups (*p < 0.05)
Fig. 6
Fig. 6
Representative SEM montages of limbal rims froma a 24-year-old donor andb a 69-year-old donor. It is clearly shown that the surface area and degrees of arc coverage of the niche features (surrounded with ared line) is reduced in the older donor
Fig. 7
Fig. 7
Representative SEM images of LEC and FSP structures ina 3-,b 24-,c 60- andd 70-year-old donors: the FSP features (white arrows) gradually become less defined with progression of age
Fig. 8
Fig. 8
a Relative telomerase activity andb relative telomere length of cultured limbal epithelial cells harvested from cadaveric donor tissue. No significant difference was observed between the different age groups
Fig. 9
Fig. 9
a Cytokeratin 15,b ΔΝp63α andc ABCG2 expression levels of cultured limbal epithelial cells harvested from cadaveric donor tissue as measured by quantitative PCR. No significant difference was observed between the different age groups
Fig. 10
Fig. 10
a %CFE of cultured limbal epithelial cells harvested from cadaveric donor tissue was significantly higher for 0–30-year-olds compared to both 30–60 and 60–90-year-olds (*p < 0.05). Representative CFE cultures of limbal epithelial cells fromb 27-,c 57- anda 78-year-old donors are shown
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