MG53 promotes corneal wound healing and mitigates fibrotic remodeling in rodents

Abstract

The cornea plays an important role in transmitting light and providing protection to the eye, but is susceptible to injury and infection. Standard treatments for corneal wounds include topical lubricants, antibiotics, bandage contact lens, and surgery. However, these measures are often ineffective. Here we show that MG53, a protein with an essential role in cell membrane repair, contributes to the corneal injury-repair process. Native MG53 is present in the corneal epithelia, tear film, and aqueous humor, suggesting its potential function in corneal homeostasis. Knockout of MG53 in mice causes impaired healing and regenerative capacity following injury. Exogenous recombinant human MG53 (rhMG53) protein protects the corneal epithelia against mechanical injury and enhances healing by promoting migration of corneal fibroblasts. Using in vivo alkaline-induced injury to the rat cornea, we show that rhMG53 promotes re-epithelialization and reduces post-injury fibrosis and vascularization. Finally, we show that rhMG53 modulates TGF-β-mediated fibrotic remodeling associated with corneal injury. Overall, our data support the bi-functional role of MG53 in facilitating corneal healing and maintaining corneal transparency by reducing fibrosis and vascularization associated with corneal injuries.

MG53 Does Not Manifest the Development of Diabetes in db/db Mice

“…6D). These findings are consistent with our published observation that rhMG53 improves wound healing as well as suppresses fibrotic remodeling in the cornea (13). The data presented here further support the physiological role for MG53 in facilitating tissue repair and regeneration even in diabetic mice-rather than a role as a compromising factor for diabetes.…”

“…We screened several stable hybridoma clones that secreted anti-MG53 antibodies. The clone used in the current study, mAb-MG53, has the highest sensitivity and has been validated in our previous publications (8,9,13,25).…”

“…Washed samples were processed and embedded in paraffin. Immunofluorescent staining of CD31 was performed using flat mount corneas following a previously published study (13,26). Parrafin section (4 mm thick) were cut as slides for immunofluorescent staining, which was performed as follows: slides were deparaffinized and rehydrated by incubating successively in xylene; 100%, 95%, 75%, and 50% ethanol; and PBS.…”

“…We previously identified a protein, mitsugumin 53 (MG53), as a main component for plasma membrane repair machinery (5). An extensive series of subsequent studies established that recombinant human (rh)MG53 protein can be used to treat injuries to multiple organs, including skeletal muscle, heart, lung, kidney, brain, cornea, and skin (6)(7)(8)(9)(10)(11)(12)(13). Many of these organs are also impacted by long-standing diabetes, suggesting that MG53 may be an ideal therapeutic agent for treating multiorgan damage in diabetes.…”

Ectodysplasin-A signaling is a key integrator in the lacrimal gland–cornea feedback loop

“…Basal tears supply the avascular corneal epithelium with growth factors necessary for its maturation and maintenance (for reviews, see Klenkler et al, 2007;Zieske, 2004). Some growth factors can originate from the aqueous humor, through the endothelium following injury (Chandler et al, 2019). Epidermal growth factor (EGF), for instance, is one of the most characterized LG-secreted factor and is known to positively regulate proliferation of corneal epithelial cells (Xiao et al, 2012).…”