Research ArticleTissue Repair

Galectin-3 initiates epithelial-stromal paracrine signaling to shape the proteolytic microenvironment during corneal repair

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Science Signaling  16 Jul 2019:
Vol. 12, Issue 590, eaaw7095
DOI: 10.1126/scisignal.aaw7095

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Epithelial-stromal paracrine signaling for corneal repair

Injuries to epithelia that breach the basement membrane allow epithelial cells to come into contact with the underlying stroma. Epithelial-stromal interactions are critical for matrix remodeling and repair of the damaged tissue. AbuSamra et al. found that contact with corneal fibroblasts stimulated corneal epithelial cells to produce the matrix metalloprotease MMP9. The carbohydrate-binding protein galectin-3 from epithelial cells stimulated fibroblasts to produce the proinflammatory cytokine IL-1β, which in turn stimulated MMP9 expression in the epithelial cells. This paracrine signaling network was required for the healing of corneal wounds in vivo only if the wounds breached the basement membrane. Because galectin-3 is associated with various tissue remodeling events, this galectin-3–induced epithelial-stromal paracrine network may also be relevant in other pathophysiological contexts in which microenvironment remodeling plays a critical role, such as cancer cell invasion and metastasis.


Paracrine interactions between epithelial cells and stromal fibroblasts occur during tissue repair, development, and cancer. Crucial to these processes is the production of matrix metalloproteinases (MMPs) that modify the microenvironment. Here, we demonstrated that the carbohydrate-binding protein galectin-3 stimulated microenvironment remodeling in the cornea by promoting the paracrine action of secreted interleukin-1β (IL-1β). Through live cell imaging in vitro, we observed rapid activation of the MMP9 promoter in clusters of cultured human epithelial cells after direct heterotypic contact with single primary human fibroblasts. Soluble recombinant galectin-3 and endogenous galectin-3 of epithelial origin both stimulated MMP9 activity through the induction of IL-1β secretion by fibroblasts. In vivo, mechanical disruption of the basement membrane in wounded corneas prompted an increase in the abundance of IL-1β in the stroma and increased the amount of gelatinase activity in the epithelium. Moreover, corneas of galectin-3–deficient mice failed to stimulate IL-1β after wounding. This mechanism of paracrine control has broad importance for our understanding of how the proteolytic microenvironment is modified in epithelial-stromal interactions.

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