Cellular Responses of Corneal Fibroblasts to Cyclic Stretching Loads
Mechanical signaling is one of the essential factors contributing to the homeostasis of connective tissues. It is important both in the maintenance of normal physiology as well as the development of pathology within many tissues. The normal turnover of mesenchymal extracellular matrix (ECM) in cornea is at a very slow balanced way in life and the integrity of highly organized collagen network that keeps cornea transparent is maintained in life. Any pathology disturbing the balanced homeostasis of the collagen network can lead to the structural perturbation and loss of corneal transparency, and therefore compromises the vision. In eyes, intraocular pressure has been proven to be essential for the normal development of eyeballs. In cornea, physical forces induced by corneal fibroblasts organize the production of unique extracellular matrices (ECM). In addition, eye rubbing, one of the commonly encountered extrinsic mechanical stimuli in daily scenario, have been shown to be strongly correlated to the development and progression of keratoconus clinically. Therefore in this work, we attempt to investigate the potential role of mechanical cues in cornea.
In this serial works, we firstly demonstrated the morphological changes of keratoconus, as well as the alterations in corneal collagenous stroma following ribroflavin/UVA crosslinking treatment, using a noninvasive MPM imaging system. We not only demonstrated the feasibility of MPM imaging system for disclosing cellular and structural information within cornea noninvasively, we also found that the architecture of stroma was altered in keratoconus, with collagen fibers directed toward the apex of cone. The result provided a clue for the role of mechanical cues in cornea. We then investigated the cellular responses of corneal fibroblasts to cyclic stretching, as the entry for deciphering the effect of mechanical cues in cornea. We found that although the morphology and alignment of corneal fibroblasts were not affected, MMP-2 and weakly MMP-9 expression were enhanced in corneal fibroblasts. The levels of MMP-2 in gene expression, protein secretion, and enzyme activity were all enhanced, and regulated through MAPK pathway. The results implicated a process of ECM modulation by corneal fibroblasts in response to cyclic stretch developed, which may therefore provide a mechanism for the correlation between eye rubbing and keratoconus. And in the supplementary works, we demonstrated the capability of noninvasive MPM system for disclosing structural information of polymeric scaffolds applied in tissue engineering, which may potentially be of valuable in studying cell-matrix interaction in the field of tissue engineering, including cornea.
Further works will be done to investigate thorough ECM modulation processes within 3D cell-seeded corneal constructs, in responses to mechanical cues, using MPM system as an effective noninvasive monitoring system. And the results may not only provide information about the role of mechanical cues in the pathogenesis of keratoconus, but also valuable information in the field of corneal tissue engineering.
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