WNT7A and PAX6 define corneal epithelium homeostasis and pathogenesis
Authors
Hong Ouyang, Yuanchao Xue, Ying Lin, Xiaohui Zhang, Lei Xi, Sherrina Patel, Huimin Cai, Jing Luo, Meixia Zhang, Ming Zhang, Yang Yang, Gen Li, Hairi Li, Wei Jiang, Emily Yeh, Jonathan Lin, Michelle Pei, Jin Zhu, Guiqun Cao, Liangfang Zhang, Benjamin Yu, Shaochen Chen, Xiang-Dong Fu, Yizhi Liu & Kang Zhang
Institution
UCSD
Country
United States
Year
2014
Journal
Nature
Abstract
The surface of the cornea consistsof a unique type ofnon-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 fromlimbal stemor
progenitor cells (LSCs)1,2,anddeficiency inLSCsor 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 worldwide3.HowLSCs are maintained and differentiated
into corneal epitheliumin 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
LSCexpansionand three-dimensional corneal differentiation protocol
inwhich wefoundthat the transcriptionfactorsp63 (tumour protein
63) andPAX6(paired box proteinPAX6)act together to specify LSCs,
and WNT7A controls corneal epithelium differentiation through
PAX6. Loss ofWNT7A 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 injurymodel, 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.