Genipin increases extracellular matrix synthesis preventing corneal perforation

The stroma comprises 90% of the corneal tissue and consists of water, and extracellular matrix─ mainly various collagens and proteoglycans [[1], [2], [3], [4]]. The structure and hierarchical organization of the corneal extracellular matrix are a major reason for its unique properties: clarity, avascularity, tissue strength and shape [[1], [2], [3], [4]]. Loss of stromal integrity caused by infection, chemical injuries or autoimmune disease (e.g., melting) can lead to corneal perforation and permanent vision loss. Full thickness corneal transplantation is the standard treatment when corneal perforation is imminent or has occurred. The long-term prognosis of corneal transplantation in the setting of active inflammation is poor [5].

Keratocytes, neural crest–derived cells that reside in the corneal stroma, are believed to play an important role in the acquisition and maintenance of the normal properties of the corneal stroma including transparency [1,6,7]. During corneal stromal development, keratocytes regulate the synthesis and deposition of extracellular matrix and organize collagen fibrils [[8], [9], [10]]. Keratocytes are mitotically quiescent and have a dendritic morphology with extensive intercellular contacts [7]. The expression of keratocan, a proteoglycan found almost exclusively in the corneal stroma, is regarded as a marker of corneal keratocyte phenotype [11,12].

During standard culture conditions on plastic dishes using fetal bovine serum, keratocytes (murine [13], bovine [14], rabbit [15], primate [16], and human [[17], [18], [19]]) lose their dendritic morphology and expression of keratocan, thereby transforming to fibroblasts without morphological or biosynthetic characters of keratocytes (e.g., shut down keratocan expression) [11,12,17]. These corneal derived fibroblasts cultured at low densities or stimulated by transforming growth factor-β1 might further differentiate into myofibroblasts [15,20]. After corneal stroma acute injuries, quiescent keratocytes are believed to activate into fibroblasts and become mitotically active increasing their collagen and extracellular matrix synthesis needed to repair injuries and close stromal defects. Such processes will preserve the integrity and function of the eyeball at the expense of corneal clarity. Eventually, fibroblasts can transform into α-smooth muscle actin-expressing myofibroblasts. Transformed fibroblasts and myofibroblasts do not express keratocan [1,21,22].

Corneal wound healing studies are focused in promoting tissue regeneration and preventing scar formation by regulating cytokines, tissue repair and immune system infiltration and response. Immediately following injury that results in loss of tissue integrity, host responses attempt to promptly restore integrity to prevent infection and loss of function. Genipin is a crosslinking compound, isolated from Gardenis jasminoides and Genipa americana. It is also known as the gardenia and genipap fruits. We and others have shown that genipin solutions can be safely used to crosslink corneal stromal with minimal risk of corneal toxicity [23,24], although a recent report suggests retinal toxicity when in direct contact with the posterior segment of the eye [25]. Previous work has shown that genipin efficiently and significantly increases corneal tissue stiffness in rabbit, porcine and human stroma [26,27]. Besides the effects on increasing tissue stiffness by cross-linking the extracellular matrix, we recently demonstrated that genipin increased tissue resistance to bacterial collagenase digestion and retards stromal melting [28].

In this project, we investigate the potential action of genipin in decreasing the risk of corneal perforation by activating stromal cells synthetic activity. We further examine a mechanism that underlies increased stromal cells extracellular matrix synthesis and describe the clinical application of genipin in a group of patients with threatening perforations.

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