Publication Date:
2014-07-18
Description:
The surface of the cornea consists of a unique type of non-keratinized epithelial cells arranged in an orderly fashion, and this is essential for vision by maintaining transparency for light transmission. Cornea epithelial cells (CECs) undergo continuous renewal from limbal stem or progenitor cells (LSCs), and deficiency in LSCs or corneal epithelium--which turns cornea into a non-transparent, keratinized skin-like epithelium--causes corneal surface disease that leads to blindness in millions of people worldwide. How LSCs are maintained and differentiated into corneal epithelium in healthy individuals and which key molecular events are defective in patients have been largely unknown. Here we report establishment of an in vitro feeder-cell-free LSC expansion and three-dimensional corneal differentiation protocol in which we found that the transcription factors p63 (tumour protein 63) and PAX6 (paired box protein PAX6) act together to specify LSCs, and WNT7A controls corneal epithelium differentiation through PAX6. Loss of WNT7A or PAX6 induces LSCs into skin-like epithelium, a critical defect tightly linked to common human corneal diseases. Notably, transduction of PAX6 in skin epithelial stem cells is sufficient to convert them to LSC-like cells, and upon transplantation onto eyes in a rabbit corneal injury model, these reprogrammed cells are able to replenish CECs and repair damaged corneal surface. These findings suggest a central role of the WNT7A-PAX6 axis in corneal epithelial cell fate determination, and point to a new strategy for treating corneal surface diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610745/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4610745/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ouyang, Hong -- Xue, Yuanchao -- Lin, Ying -- Zhang, Xiaohui -- Xi, Lei -- Patel, Sherrina -- Cai, Huimin -- Luo, Jing -- Zhang, Meixia -- Zhang, Ming -- Yang, Yang -- Li, Gen -- Li, Hairi -- Jiang, Wei -- Yeh, Emily -- Lin, Jonathan -- Pei, Michelle -- Zhu, Jin -- Cao, Guiqun -- Zhang, Liangfang -- Yu, Benjamin -- Chen, Shaochen -- Fu, Xiang-Dong -- Liu, Yizhi -- Zhang, Kang -- GM049369/GM/NIGMS NIH HHS/ -- R01 EY020846/EY/NEI NIH HHS/ -- R01 EY021374/EY/NEI NIH HHS/ -- England -- Nature. 2014 Jul 17;511(7509):358-61. doi: 10.1038/nature13465. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing 100730, China (X.Z.); Department of Ophthalmology, Shengjing Hospital of China Medical University, Shenyang 110004, China (Y.Y.). ; Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China. ; 1] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California San Diego, La Jolla, California 92093, USA. ; 1] Department of Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA [3] Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology, and Biomaterial and Tissue Engineering Center of Institute of Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [3] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China [4] Institute for Genomic Medicine, University of California San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25030175" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Differentiation
;
Cell Lineage
;
Corneal Diseases/*metabolism/*pathology
;
Disease Models, Animal
;
Epithelium, Corneal/*cytology/*metabolism/pathology
;
Eye Proteins/genetics/*metabolism
;
Homeodomain Proteins/genetics/*metabolism
;
*Homeostasis
;
Humans
;
Limbus Corneae/cytology/metabolism
;
Male
;
Paired Box Transcription Factors/genetics/*metabolism
;
Rabbits
;
Repressor Proteins/genetics/*metabolism
;
Signal Transduction
;
Skin/cytology/metabolism/pathology
;
Stem Cell Transplantation
;
Stem Cells/cytology/metabolism
;
Transcription Factors/metabolism
;
Tumor Suppressor Proteins/metabolism
;
Wnt Proteins/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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