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Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia
We aimed to test previous predictions that limbal epithelial stem cells (LESCs) are quantitatively deficient or qualitatively defective in Pax6(+/−) mice and decline with age in wild-type (WT) mice. Consistent with previous studies, corneal epithelial stripe patterns coarsened with age in WT mosaics...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742784/ https://www.ncbi.nlm.nih.gov/pubmed/23967157 http://dx.doi.org/10.1371/journal.pone.0071117 |
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author | Douvaras, Panagiotis Mort, Richard L. Edwards, Dominic Ramaesh, Kanna Dhillon, Baljean Morley, Steven D. Hill, Robert E. West, John D. |
author_facet | Douvaras, Panagiotis Mort, Richard L. Edwards, Dominic Ramaesh, Kanna Dhillon, Baljean Morley, Steven D. Hill, Robert E. West, John D. |
author_sort | Douvaras, Panagiotis |
collection | PubMed |
description | We aimed to test previous predictions that limbal epithelial stem cells (LESCs) are quantitatively deficient or qualitatively defective in Pax6(+/−) mice and decline with age in wild-type (WT) mice. Consistent with previous studies, corneal epithelial stripe patterns coarsened with age in WT mosaics. Mosaic patterns were also coarser in Pax6(+/−) mosaics than WT at 15 weeks but not at 3 weeks, which excludes a developmental explanation and strengthens the prediction that Pax6(+/−) mice have a LESC-deficiency. To investigate how Pax6 genotype and age affected corneal homeostasis, we compared corneal epithelial cell turnover and label-retaining cells (LRCs; putative LESCs) in Pax6(+/−) and WT mice at 15 and 30 weeks. Limbal BrdU-LRC numbers were not reduced in the older WT mice, so this analysis failed to support the predicted age-related decline in slow-cycling LESC numbers in WT corneas. Similarly, limbal BrdU-LRC numbers were not reduced in Pax6(+/−) heterozygotes but BrdU-LRCs were also present in Pax6(+/−) corneas. It seems likely that Pax6(+/−) LRCs are not exclusively stem cells and some may be terminally differentiated CD31-positive blood vessel cells, which invade the Pax6(+/−) cornea. It was not, therefore, possible to use this approach to test the prediction that Pax6(+/−) corneas had fewer LESCs than WT. However, short-term BrdU labelling showed that basal to suprabasal movement (leading to cell loss) occurred more rapidly in Pax6(+/−) than WT mice. This implies that epithelial cell loss is higher in Pax6(+/−) mice. If increased corneal epithelial cell loss exceeds the cell production capacity it could cause corneal homeostasis to become unstable, resulting in progressive corneal deterioration. Although it remains unclear whether Pax6(+/−) mice have LESC-deficiency, we suggest that features of corneal deterioration, that are often taken as evidence of LESC-deficiency, might occur in the absence of stem cell deficiency if corneal homeostasis is destabilised by excessive cell loss. |
format | Online Article Text |
id | pubmed-3742784 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37427842013-08-21 Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia Douvaras, Panagiotis Mort, Richard L. Edwards, Dominic Ramaesh, Kanna Dhillon, Baljean Morley, Steven D. Hill, Robert E. West, John D. PLoS One Research Article We aimed to test previous predictions that limbal epithelial stem cells (LESCs) are quantitatively deficient or qualitatively defective in Pax6(+/−) mice and decline with age in wild-type (WT) mice. Consistent with previous studies, corneal epithelial stripe patterns coarsened with age in WT mosaics. Mosaic patterns were also coarser in Pax6(+/−) mosaics than WT at 15 weeks but not at 3 weeks, which excludes a developmental explanation and strengthens the prediction that Pax6(+/−) mice have a LESC-deficiency. To investigate how Pax6 genotype and age affected corneal homeostasis, we compared corneal epithelial cell turnover and label-retaining cells (LRCs; putative LESCs) in Pax6(+/−) and WT mice at 15 and 30 weeks. Limbal BrdU-LRC numbers were not reduced in the older WT mice, so this analysis failed to support the predicted age-related decline in slow-cycling LESC numbers in WT corneas. Similarly, limbal BrdU-LRC numbers were not reduced in Pax6(+/−) heterozygotes but BrdU-LRCs were also present in Pax6(+/−) corneas. It seems likely that Pax6(+/−) LRCs are not exclusively stem cells and some may be terminally differentiated CD31-positive blood vessel cells, which invade the Pax6(+/−) cornea. It was not, therefore, possible to use this approach to test the prediction that Pax6(+/−) corneas had fewer LESCs than WT. However, short-term BrdU labelling showed that basal to suprabasal movement (leading to cell loss) occurred more rapidly in Pax6(+/−) than WT mice. This implies that epithelial cell loss is higher in Pax6(+/−) mice. If increased corneal epithelial cell loss exceeds the cell production capacity it could cause corneal homeostasis to become unstable, resulting in progressive corneal deterioration. Although it remains unclear whether Pax6(+/−) mice have LESC-deficiency, we suggest that features of corneal deterioration, that are often taken as evidence of LESC-deficiency, might occur in the absence of stem cell deficiency if corneal homeostasis is destabilised by excessive cell loss. Public Library of Science 2013-08-13 /pmc/articles/PMC3742784/ /pubmed/23967157 http://dx.doi.org/10.1371/journal.pone.0071117 Text en © 2013 Douvaras et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Douvaras, Panagiotis Mort, Richard L. Edwards, Dominic Ramaesh, Kanna Dhillon, Baljean Morley, Steven D. Hill, Robert E. West, John D. Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia |
title | Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia |
title_full | Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia |
title_fullStr | Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia |
title_full_unstemmed | Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia |
title_short | Increased Corneal Epithelial Turnover Contributes to Abnormal Homeostasis in the Pax6(+/−) Mouse Model of Aniridia |
title_sort | increased corneal epithelial turnover contributes to abnormal homeostasis in the pax6(+/−) mouse model of aniridia |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742784/ https://www.ncbi.nlm.nih.gov/pubmed/23967157 http://dx.doi.org/10.1371/journal.pone.0071117 |
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