Limbal Stem Cell Dysfunction Induced by Severe Dry Eye via Activation of the p38 MAPK Signaling Pathway.

Severe dry eye (SDE) can cause grievous damage of the ocular surface and result in vision impairment and even blindness. To investigate the fate of limbal stem cells in SDE and the underlying mechanism, we established an SDE rat model by removing the extra orbital and infraorbital lacrimal glands and maintained it in a low-humidity environment. One month after the operation, aqueous tear secretion dramatically reduced, blood vessels invaded into the central cornea, and inflammatory cells infiltrated into the limbal stroma. The expression of K12 and Pax6 was dramatically down-regulated, while those of K10, Sprr1b, and MUC5AC were up-regulated in the corneal epithelium of the SDE rats. Cell proliferation in the limbal epithelium was up-regulated, while the stem/progenitor marker ABCG2 and the limbal epithelial colony-forming efficiency was decreased under the SDE condition. Furthermore, the p38 MAPK signaling pathway was activated in the limbal corneal epithelium of the SDE rats. The abnormal differentiation and stemness loss in the cornea epithelium could be reversed upon treatment with a p38 inhibitor in SDE in vivo model and in vitro hyperosmolar corneal epithelial culture condition. In conclusion, severe dry eye can lead to limbal stem cell dysfunction, and p38 MAPK signaling pathway activation plays an essential role in this process.