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SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium

Mutations in key transcription factors SOX2 and P63 were linked with developmental defects and postnatal abnormalities such as corneal opacification, neovascularization, and blindness. The latter phenotypes suggest that SOX2 and P63 may be involved in corneal epithelial regeneration. Although P63 ha...

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Autores principales: Bhattacharya, Swarnabh, Serror, Laura, Nir, Eshkar, Dhiraj, Dalbir, Altshuler, Anna, Khreish, Maroun, Tiosano, Beatrice, Hasson, Peleg, Panman, Lia, Luxenburg, Chen, Aberdam, Daniel, Shalom‐Feuerstein, Ruby
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850148/
https://www.ncbi.nlm.nih.gov/pubmed/30548157
http://dx.doi.org/10.1002/stem.2959
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author Bhattacharya, Swarnabh
Serror, Laura
Nir, Eshkar
Dhiraj, Dalbir
Altshuler, Anna
Khreish, Maroun
Tiosano, Beatrice
Hasson, Peleg
Panman, Lia
Luxenburg, Chen
Aberdam, Daniel
Shalom‐Feuerstein, Ruby
author_facet Bhattacharya, Swarnabh
Serror, Laura
Nir, Eshkar
Dhiraj, Dalbir
Altshuler, Anna
Khreish, Maroun
Tiosano, Beatrice
Hasson, Peleg
Panman, Lia
Luxenburg, Chen
Aberdam, Daniel
Shalom‐Feuerstein, Ruby
author_sort Bhattacharya, Swarnabh
collection PubMed
description Mutations in key transcription factors SOX2 and P63 were linked with developmental defects and postnatal abnormalities such as corneal opacification, neovascularization, and blindness. The latter phenotypes suggest that SOX2 and P63 may be involved in corneal epithelial regeneration. Although P63 has been shown to be a key regulator of limbal stem cells, the expression pattern and function of SOX2 in the adult cornea remained unclear. Here, we show that SOX2 regulates P63 to control corneal epithelial stem/progenitor cell function. SOX2 and P63 were co‐expressed in the stem/progenitor cell compartments of the murine cornea in vivo and in undifferentiated human limbal epithelial stem/progenitor cells in vitro. In line, a new consensus site that allows SOX2‐mediated regulation of P63 enhancer was identified while repression of SOX2 reduced P63 expression, suggesting that SOX2 is upstream to P63. Importantly, knockdown of SOX2 significantly attenuated cell proliferation, long‐term colony‐forming potential of stem/progenitor cells, and induced robust cell differentiation. However, this effect was reverted by forced expression of P63, suggesting that SOX2 acts, at least in part, through P63. Finally, miR‐450b was identified as a direct repressor of SOX2 that was required for SOX2/P63 downregulation and cell differentiation. Altogether, we propose that SOX2/P63 pathway is an essential regulator of corneal stem/progenitor cells while mutations in SOX2 or P63 may disrupt epithelial regeneration, leading to loss of corneal transparency and blindness. Stem Cells 2019;37:417–429
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spelling pubmed-68501482019-11-15 SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium Bhattacharya, Swarnabh Serror, Laura Nir, Eshkar Dhiraj, Dalbir Altshuler, Anna Khreish, Maroun Tiosano, Beatrice Hasson, Peleg Panman, Lia Luxenburg, Chen Aberdam, Daniel Shalom‐Feuerstein, Ruby Stem Cells Tissue‐Specific Stem Cells Mutations in key transcription factors SOX2 and P63 were linked with developmental defects and postnatal abnormalities such as corneal opacification, neovascularization, and blindness. The latter phenotypes suggest that SOX2 and P63 may be involved in corneal epithelial regeneration. Although P63 has been shown to be a key regulator of limbal stem cells, the expression pattern and function of SOX2 in the adult cornea remained unclear. Here, we show that SOX2 regulates P63 to control corneal epithelial stem/progenitor cell function. SOX2 and P63 were co‐expressed in the stem/progenitor cell compartments of the murine cornea in vivo and in undifferentiated human limbal epithelial stem/progenitor cells in vitro. In line, a new consensus site that allows SOX2‐mediated regulation of P63 enhancer was identified while repression of SOX2 reduced P63 expression, suggesting that SOX2 is upstream to P63. Importantly, knockdown of SOX2 significantly attenuated cell proliferation, long‐term colony‐forming potential of stem/progenitor cells, and induced robust cell differentiation. However, this effect was reverted by forced expression of P63, suggesting that SOX2 acts, at least in part, through P63. Finally, miR‐450b was identified as a direct repressor of SOX2 that was required for SOX2/P63 downregulation and cell differentiation. Altogether, we propose that SOX2/P63 pathway is an essential regulator of corneal stem/progenitor cells while mutations in SOX2 or P63 may disrupt epithelial regeneration, leading to loss of corneal transparency and blindness. Stem Cells 2019;37:417–429 John Wiley & Sons, Inc. 2019-02-01 2019-03 /pmc/articles/PMC6850148/ /pubmed/30548157 http://dx.doi.org/10.1002/stem.2959 Text en © 2018 The Authors. stem cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press 2018 This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Tissue‐Specific Stem Cells
Bhattacharya, Swarnabh
Serror, Laura
Nir, Eshkar
Dhiraj, Dalbir
Altshuler, Anna
Khreish, Maroun
Tiosano, Beatrice
Hasson, Peleg
Panman, Lia
Luxenburg, Chen
Aberdam, Daniel
Shalom‐Feuerstein, Ruby
SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium
title SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium
title_full SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium
title_fullStr SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium
title_full_unstemmed SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium
title_short SOX2 Regulates P63 and Stem/Progenitor Cell State in the Corneal Epithelium
title_sort sox2 regulates p63 and stem/progenitor cell state in the corneal epithelium
topic Tissue‐Specific Stem Cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850148/
https://www.ncbi.nlm.nih.gov/pubmed/30548157
http://dx.doi.org/10.1002/stem.2959
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