Abstract
The corneal epithelium mediates the initial response to injury of the ocular surface and secretes a number of profibrotic factors that promote corneal scar development within the stroma. Previous studies have shown that corneal epithelial cells also secrete small extracellular vesicles (EVs) in response to corneal wounding. In this paper, we hypothesized that EVs released from corneal epithelial cells in vitro contain protein cargo that promotes myofibroblast differentiation, the key cell responsible for scar development. We focused on the interplay between corneal epithelial-derived EVs and the stroma to determine if the corneal fibroblast phenotype, contraction, proliferation, or migration were promoted following vesicle uptake by corneal fibroblasts. Our results showed an increase in myofibroblast differentiation based on α-smooth muscle actin expression and elevated contractility following EV treatment compared to controls. Furthermore, we characterized the contents of epithelial cell-derived EVs using proteomic analysis and identified the presence of provisional matrix proteins, fibronectin and thrombospondin-1, as the dominant encapsulated protein cargo secreted by corneal epithelial cells in vitro. Proteins associated with the regulation of protein translation were also abundant in EVs. This paper reveals a novel role and function of EVs secreted by the corneal epithelium that may contribute to corneal scarring.
Highlights
Corneal scarring affects over 4.9 million people worldwide as a leading cause of blindness [1]and may develop in response to injury, infection, or genetic corneal dystrophies [2]
Our current study examined extracellular vesicles (EVs) secreted by human corneal epithelial cells in vitro and their functional effects on fibroblast contraction, proliferation, migration, and the phenotype
We compared EVs isolated from unwounded control versus debrided corneal epithelium, and verified the expression of a common EV marker, CD63 [39,40,41], in isolated EVs using Western blot (Figure 1C)
Summary
Corneal scarring affects over 4.9 million people worldwide as a leading cause of blindness [1]and may develop in response to injury, infection, or genetic corneal dystrophies [2]. Corneal scarring decreases vision by inducing tissue opacity that blocks light from entering the eye, and frequently distorts the shape of the cornea, which results in irregular astigmatism and higher order aberrations. While these irregularities in the cornea can often be corrected by hard contact lenses, opacities within the tissue necessitate surgery, such as corneal transplantation, in order to restore the eye’s visual potential. Resident corneal cell populations (e.g., epithelium, keratocyte, neuronal, and immune cells) mediate the collective corneal tissue response to injury via autocrine and exocrine signaling that influences clinical outcome, such as corneal scar development, persistent pain, and tissue regeneration [7]. As the anterior cell surface of the eye, the corneal epithelium expresses various soluble
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