Age Dependent Changes in Corneal Epithelial Cell Signaling

Abstract

The cornea is exposed daily to a number of mechanical stresses including shear stress from tear film and blinking. Over time, these stressors can lead to changes in the extracellular matrix that alter corneal stiffness, cell-substrate structures, and the integrity of cell-cell junctions. We hypothesized that changes in tissue stiffness of the cornea with age may alter calcium signaling between cells after injury, and the downstream effects of this signaling on cellular motility and wound healing. Nanoindentation studies revealed that there were significant differences in the stiffness of the corneal epithelium and stroma between corneas of 9- and 27-week mice. These changes corresponded to differences in the timeline of wound healing and in cell signaling. Corneas from 9-week mice were fully healed within 24 h. However, the wounds on corneas from 27-week mice remained incompletely healed. Furthermore, in the 27-week cohort there was no detectable calcium signaling at the wound in either apical or basal corneal epithelial cells. This is in contrast to the young cohort, where there was elevated basal cell activity relative to background levels. Cell culture experiments were performed to assess the roles of P2Y2, P2X7, and pannexin-1 in cellular motility during wound healing. Inhibition of P2Y2, P2X7, or pannexin-1 all significantly reduce wound closure. However, the inhibitors all have different effects on the trajectories of individual migrating cells. Together, these findings suggest that there are several significant differences in the stiffness and signaling that underlie the decreased wound healing efficacy of the cornea in older mice.

Age-Related Differences in the Mouse Corneal Epithelial Transcriptome and Their Impact on Corneal Wound Healing

“…Previous studies showed that 27-week-old B6 mice cornea wounds healed more slowly than 9-week-old B6 mice corneas over the first 24 hours. 121 Likewise, in humans, corneal epithelial wound healing is delayed in aged individuals compared with younger people, possibly owing to a decrease in the regenerative capacity of the corneal epithelial cells. 122 Another possible reason is that aging corneal epithelial cells may exhibit changes in their cellular response to injury or inflammation that can lead to prolonged inflammation and, consequently, delayed healing.…”

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

“…In the cornea, pannexin 1 is decreased in stromal nerves as demonstrated in a mouse model (Cui et al., 2016; Rhodes et al., 2021). When the corneal epithelium (surrogate Schwann cells of corneal nerves) is injured or infected, injured cells release ATP via pannexin 1, which initiates calcium signaling events in the cornea and the tear film (Cui et al., 2016; Rhodes et al., 2021; Segars et al., 2022; Yang et al., 2019). Future studies are required to elucidate the exact role of pannexin 1 in corneal neuropathic pain.…”

“…Furthermore, when mast cells are activated, they secrete tryptase and interleukin-17, which instigate the activation of the protease-activated receptor-2 pathway on nerves, which fosters neurogenic inflammation and subsequent pain (Aich et al, 2015;Duchesne et al, 2011;Kulka et al, 2008). IL-17A receptors have been expressed and produced by nociceptor neurons and play an integral role by altering the expression of TRPV4 channels required in pain perception (Segond von Banchet et al, 2013).…”

Experimental Analysis of Tear Fluid and Its Processing for the Diagnosis of Multiple Sclerosis

“…Tears lubricate the ocular surface, carrying secreted molecules from corneal epithelial cells [10]. Tears represent the whole physiological status of the body [11,12].…”