Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 1, Pages 385-397Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI71488
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Funding
- Japanese Ministry of Education, Culture, Sports, Science and Technology [23592621]
- JST-ETH Strategic Japanese-Swiss Cooperative Program [Heisei 20]
- CHUV, OptiStem
- BBSRC (UK)
- EPFL
- Grants-in-Aid for Scientific Research [24592675, 23390404] Funding Source: KAKEN
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Corneal integrity and transparency are indispensable for good vision. Cornea homeostasis is entirely dependent upon corneal stem cells, which are required for complex wound-healing processes that restore corneal integrity following epithelial damage. Here, we found that leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is highly expressed in the human holoclone-type corneal epithelial stem cell population and sporadically expressed in the basal cells of ocular-surface epithelium. In murine models, LRIG1 regulated corneal epithelial cell fate during wound repair. Deletion of Lrig1 resulted in impaired stem cell recruitment following injury and promoted a cell-fate switch from transparent epithelium to keratinized skin-like epidermis, which led to corneal blindness. In addition, we determined that LRIG1 is a negative regulator of the STAT3-dependent inflammatory pathway. Inhibition of STAT3 in corneas of Lrig1(-/-) mice rescued pathological phenotypes and prevented corneal opacity. Additionally, transgenic mice that expressed a constitutively active form of STAT3 in the corned epithelium had abnormal features, including corneal plaques and neovascularization similar to that found in Lrig1(-/-) mice. Bone marrow chimera experiments indicated that LRIG1 also coordinates the function of bone marrow-derived inflammatory cells. Together, our data indicate that LRIG1 orchestrates corned-tissue transparency and cell fate during repair, and identify LRIG1 as a key regulator of tissue homeostasis.
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