Opposing Effects of Neuropilin-1 and -2 on Sensory Nerve Regeneration in Wounded Corneas: Role of Sema3C in Ameliorating Diabetic Neurotrophic Keratopathy

Abstract

The diabetic cornea exhibits pathological alterations, such as delayed epithelial wound healing and nerve regeneration. We investigated the role of semaphorin (SEMA) 3C in corneal wound healing and reinnervation in normal and diabetic B6 mice. Wounding induced the expression of SEMA3A, SEMA3C, and their receptor neuropilin-2 (NRP2), but not NRP1, in normal corneal epithelial cells; this upregulation was suppressed for SEMA3C and NRP2 in diabetic corneas. Injections of Sema3C- specific small interfering RNA and NRP2-neutralizing antibodies in wounded mice resulted in a decrease in the rate of wound healing and regenerating nerve fibers, whereas exogenous SEMA3C had opposing effects in diabetic corneas. NRP1 neutralization, on the other hand, decreased epithelial wound closure but increased sensory nerve regeneration in diabetic corneas, suggesting a detrimental role in nerve regeneration. Taken together, epithelium-expressed SEMA3C plays a role in corneal epithelial wound closure and sensory nerve regeneration. The hyperglycemia-suppressed SEMA3C/NRP2 signaling may contribute to the pathogenesis of diabetic neurotrophic keratopathy, and SEMA3C might be used as an adjunctive therapeutic for treating the disease.

MANF Promotes Diabetic Corneal Epithelial Wound Healing and Nerve Regeneration by Attenuating Hyperglycemia-Induced Endoplasmic Reticulum Stress

“…Experiments with two treatments and/or conditions were analyzed using a twotailed Student t test. Experiments with more than two groups were analyzed using one-way ANOVA, and if the experiments involved two independent variables (e.g., normal and diabetic, unwounded and wounded), a twoway ANOVA was used (8). Differences were considered statistically significant at P , 0.05.…”

“…Patients with diabetes often present with decreased corneal wound healing, reduced corneal innervation, and a loss of corneal sensitivity (1)(2)(3)(4)(5)(6)(7)(8)(9). These complications of diabetes in the cornea are known as diabetic keratopathy (DK), which can lead to severe visual impairment (10).…”

The Role of Semaphorins in Metabolic Disorders

“…Nrp1, Nrp2 [108,109] Sema3A Not mentioned [110,111] Sema6A Not mentioned [112] Diabetic wound healing Sema4D PlexinB2 [113] Sema6A Not mentioned [114] Diabetic osteoporosis Sema3A Not mentioned [115][116][117][118]…”

“…Wounding induced the expression of Sema3A, Sema3C, and their receptor Nrp2 in normal corneal epithelial cells, but the upregulation was inhibited in diabetic cornea. Exogenous Sema3C resulted in an increased rate of wound healing and nerve fiber regeneration, while Sema3C shRNAs and Nrp2-neutralizing antibodies had opposing effects to Sema3C in diabetic cornea [109]. Sema3C is also highly expressed in inflamed tissue in Charcot foot patients [108].…”

Vinaxanthone inhibits Semaphorin3A induced axonal growth cone collapse in embryonic neurons but fails to block its growth promoting effects on adult neurons

“…Contrary to its inhibitory effects on embryonic neurons, we found that Sema3A is as effective as NGF in promoting neuronal elongation and branching in isolated adult PNS neurons and expedites nerve regeneration in vivo in mice that have undergone corneal subbasal nerve injury. Other groups have also found that supplementation with related Semaphorin proteins after corneal injury leads to improvement in epithelial and neuronal healing, including Sema3C and Sema 7A 13 , 14 .…”