These findings suggest that the microenvironment must provide tissue-specific signals that allow corneal epithelial cells to change their phenotypes. blindness. In addition, we determined that LRIG1 is a negative regulator of the STAT3-dependent inflammatory pathway. Inhibition of STAT3 in corneas ofLrig1/mice rescued pathological phenotypes and prevented corneal opacity. Additionally, transgenic mice that expressed a constitutively active form of STAT3 in the corneal epithelium had abnormal features, including corneal plaques and neovascularization similar to that found inLrig1/mice. Bone marrow chimera experiments indicated that LRIG1 also coordinates the function of bone marrowderived inflammatory cells. Together, our data indicate that LRIG1 orchestrates corneal-tissue transparency and cell fate during repair, and identify LRIG1 as a key regulator of tissue homeostasis. == Introduction == In mammals, most external information is accumulated through visual systems, and integrity of the cornea is well known to be indispensable for good vision (1). During evolution, nature has found a way to develop a well-ordered visual system to maintain corneal tissue transparency and homeostasis. The cornea is a unique avascular and transparent epithelial tissue that harbors stem cells that control homeostasis and tissue regeneration after injury (2,3). However, the homeostatic turnover of corneal epithelial tissue can become disrupted depending on the severity of damage to the corneal epithelium, resulting in collateral chronic inflammation and impaired tissue repair (4,5). These inflammation-associated processes reportedly interfere with corneal transparency and the corneas barrier function (6). It is well known that stem cells work to maintain the self renewal and repair of tissues and organs (7,8). Under normal conditions, the corneal epithelial tissue accommodates the homeostatic turnover of corneal stem cells, which is essential for postinjury tissue regeneration. Previous studies have reported that corneal epithelial stem cells reside in the basal layer of the limbal zone of the peripheral cornea (9,10). The corneal epithelial stem cell system is one of the most clearly defined systems and is therefore an ideal model for investigating the role of regulatory molecules associated with stem cell tissue repair (2,3). However, the molecular interplay between corneal epithelial stem cells and other players with critical roles in the regulation of tissue repair has yet to be elucidated. Barrandon et al. previously reported the existence of 3 types of epidermal keratinocytes with different self-renewal capacities (11). Similar behavior has subsequently been reported for corneal keratinocytes (12). Holoclones (stem cells) have the highest reproductive capacity, while in paraclones (transient amplifying cells), terminal differentiation is observed within a few generations. However, the molecular mechanism and gene expression profile of holoclone-type stem cells are entirely unknown. Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a transmembrane glycoprotein recently Mouse monoclonal antibody to CDK4. The protein encoded by this gene is a member of the Ser/Thr protein kinase family. This proteinis highly similar to the gene products of S. cerevisiae cdc28 and S. pombe cdc2. It is a catalyticsubunit of the protein kinase complex that is important for cell cycle G1 phase progression. Theactivity of this kinase is restricted to the G1-S phase, which is controlled by the regulatorysubunits D-type cyclins and CDK inhibitor p16(INK4a). This kinase was shown to be responsiblefor the phosphorylation of retinoblastoma gene product (Rb). Mutations in this gene as well as inits related proteins including D-type cyclins, p16(INK4a) and Rb were all found to be associatedwith tumorigenesis of a variety of cancers. Multiple polyadenylation sites of this gene have beenreported reported as a potential master regulator of epidermal and intestinal epithelial stem cells (1317). However, there are no reports to date that address the tissue-specific function of LRIG1 in the cornea. The findings of this present study demonstrate that Luminol LRIG1 was highly expressed in the holoclone-type corneal epithelial stem cells and that it was essential for the cell-fate maintenance of corneal epithelium during tissue repair. Loss ofLrig1impaired wound-induced corneal stem/progenitor cell replacement and resulted in a cell-fate change from corneal to keratinized epithelium. Intriguingly, we found that LRIG1 controlled the corneal Luminol cell fate during repair by negatively regulating the Stat3-dependent inflammatory pathway. Moreover, corneal cell fate during repair was not only maintained by corneal epithelial stem/progenitor cells, but also by BM-derived inflammatory cells, whose functions are well-regulated by the LRIG1/STAT3 inflammatory pathway. Thus, the findings of this present study provide new insights into the underlying homeostatic regulation of corneal keratinocyte stem/progenitor cells by LRIG1. == Results == == Gene expression profile of holoclone-type corneal keratinocyte stem cells. == In order to gain insight into the mechanisms responsible for the homeostasis within epithelial stem cells, Luminol we performed gene expression profiling of holoclone-type and Luminol paraclone-type human corneal keratinocytes. This led to the identification of 15 genes that were upregulated at least 5-fold in holoclone-type corneal epithelial stem cells (Supplemental Tables 1 and 2; supplemental material available online with this article; doi:10.1172/JCI71488DS1). We next examined the expression pattern of these genes using immunohistochemistry and identifiedLrig1for further investigation, because LRIG1 was specifically expressed in human limbal basal cells and rarely expressed in the differentiated central corneal epithelium (Figure1A). In contrast, in mouse eyes, LRIG1 was only found to be sporadically.