Abstract
Corneal wound healing depends on extracellular matrix (ECM) and topographical cues that modulate migration and proliferation of regenerating cells. In our study, silk films with either flat or nanotopography patterned parallel ridge widths of 2000, 1000, 800 nm surfaces were combined with ECMs which include collagen type I (collagen I), fibronectin, laminin, and Poly-d-Lysine to accelerate corneal wound healing. Silk films with 800 nm ridge width provided better cell spreading and wound recovery than other size topographies. Coating 800 nm patterned silk films with collagen I proves to optimally further increased mouse and rabbit corneal epithelial cells growth and wound recovery. This enhanced cellular response correlated with redistribution and increase in size and total amount of focal adhesion. Transcriptomics and signaling pathway analysis suggested that silk topography regulates cell behaviors via actin nucleation ARP-WASP complex pathway, which regulate filopodia formation. This mechanism was further explored and inhibition of Cdc42, a key protein in this pathway, delayed wound healing and decreased the length, density, and alignment of filopodia. Inhibition of Cdc42 in vivo resulted in delayed re-epithelization of injured corneas. We conclude that silk film nanotopography in combination with collagen I constitutes a better substrate for corneal wound repair than either nanotopography or ECM alone.
Highlights
Corneal wound healing depends on extracellular matrix (ECM) and topographical cues that modulate migration and proliferation of regenerating cells
Our recent studies shown that human corneal epithelial cells grown on silk film nanotopographies, differentially expressed genes involved in actin organization, integrin signaling, and focal adhesion kinase signaling and maintain corneal epithelial stem cells at a less differentiated state[15,16]
The majority of Mouse corneal epithelial cells (MCEC) were round on glass or flat silk film surfaces, while on the silk topographies the cells were elongated and aligned parallel to the direction of the patterned features (Fig. 1B)
Summary
Corneal wound healing depends on extracellular matrix (ECM) and topographical cues that modulate migration and proliferation of regenerating cells. Damage to the ocular surface can occur by traumatic, chemical, surgical or immune-conditions, resulting in injuries of the corneal epithelium, which requires mechanochemical signals to promote wound healing In this regenerative process, the corneal epithelial basement membrane, a layered cell-adherent ECM, provides biochemical and topographic features to allow for epithelial cell attachment and migration. Our recent studies shown that human corneal epithelial cells grown on silk film nanotopographies, differentially expressed genes involved in actin organization, integrin signaling, and focal adhesion kinase signaling and maintain corneal epithelial stem cells at a less differentiated state[15,16] From these previous findings, we hypothesized that silk topographies provide physical cues that may influence cellular adherence and migration by mechanisms related to cytoskeleton rearrangement
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