A Novel Mouse Model for Neurotrophic Keratopathy: Trigeminal Nerve Stereotactic Electrolysis through the Brain

Ferrari, Giulio; Chauhan, Sunil; Ueno, Hiroki; Nallasamy, Nambi; Gandolfi, Stefano; Borges, Lawrence F.; Dana, Reza

doi:10.1167/iovs.10-5688

Cited by 71 publications

(72 citation statements)

References 41 publications

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“…To assess the role of sensory nerve in corneal hemostasis, trigeminal denervation was performed24, resulting in a marked decrease in tear secretion (Fig. 6A) and the loss of corneal sensitivity (data not shown) at 1 day post-surgery.…”

Section: Resultsmentioning

confidence: 99%

Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea

Gao

Lee

2016

Sci Rep

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The corneal epithelium consists of stratified epithelial cells, sparsely interspersed with dendritic cells (DCs) and a dense layer of sensory axons. We sought to assess the structural and functional correlation of DCs and sensory nerves. Two morphologically different DCs, dendriform and round-shaped, were detected in the corneal epithelium. The dendriform DCs were located at the sub-basal space where the nerve plexus resides, with DC dendrites crossing several nerve endings. The round-shaped DCs were closely associated with nerve fiber branching points, penetrating the basement membrane and reaching into the stroma. Phenotypically, the round-shaped DCs were CD86 positive. Trigeminal denervation resulted in epithelial defects with or without total tarsorrhaphy, decreased tear secretion, and the loss of dendriform DCs at the ocular surface. Local DC depletion resulted in a significant decrease in corneal sensitivity, an increase in epithelial defects, and a reduced density of nerve endings at the center of the cornea. Post-wound nerve regeneration was also delayed in the DC-depleted corneas. Taken together, our data show that DCs and sensory nerves are located in close proximity. DCs may play a role in epithelium innervation by accompanying the sensory nerve fibers in crossing the basement membrane and branching into nerve endings.

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Section: Resultsmentioning

confidence: 99%

Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea

Gao

Lee

2016

Sci Rep

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“…The nerve cell bodies for the ICNs are located in the trigeminal ganglion (Lopez de Armentia et al, 2000). When damage to the trigeminal ganglion occurs or majority of the ICNs are severed, corneal sensitivity is lost, the corneal epithelium erodes, stroma becomes cloudy, and epithelial cells cease proliferating (Ferrari et al, 2011, 2013; Yamaguchi et al, 2013); ICNs are vital for maintaining a healthy ocular surface.…”

Section: Introductionmentioning

confidence: 99%

Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

Stepp

Pal‐Ghosh

Tadvalkar

et al. 2018

Experimental Eye Research

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Dry Eye disease causes discomfort and pain in millions of patients. Using a mouse acute desiccating stress (DS) model we show that DS induces a reduction in intraepithelial corneal nerve (ICN) density, corneal sensitivity, and apical extension of the intraepithelial nerve terminals (INTs) that branch from the subbasal nerves (SBNs). Topical application of 0.02% Mitomycin C (MMC) or vehicle alone has no impact on the overall loss of axon density due to acute DS. Chronic dry eye, which develops progressively as C57BL/6 mice age, is accompanied by significant loss of the ICNs and corneal sensitivity between 2 and 24 months of age. QPCR studies show that mRNAs for several proteins that regulate axon growth and extension are reduced in corneal epithelial cells by 24 months of age but those that regulate phagocytosis and autophagy are not altered. Taken together, these data demonstrate that dry eye disease is accompanied by alterations in intraepithelial sensory nerve morphology and function and by reduced expression in corneal epithelial cells of mRNAs encoding genes mediating axon extension.

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“…14 Partial or complete loss of corneal sensation or denervation leads to impaired corneal epithelial homeostasis owing to the lack of these neuropeptides. It has recently been shown that denervation induces apoptosis of corneal epithelial cells 31 and reduction of epithelial cell mitosis. 32 Corneal wound healing and permeability are also effected.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the reduced number of superficial epithelial cells and the increased hyperreflectivity may be attributable to extensive apoptotic response widely seen in denervated corneas. 31 On the other hand, a proliferative response is triggered to balance apoptosis in denervated corneas. This response may explain why we did not see a decrease in the basal epithelial layer.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Confocal Microscopic Changes of the Corneal Epithelium and Stroma in Patients With Herpes Zoster Ophthalmicus

Hamrah

Şahin

Dastjerdi

et al. 2015

American Journal of Ophthalmology

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Purpose To analyze the density and morphology of corneal epithelial cells and keratocytes by in vivo confocal microscopy (IVCM) in patients with herpes zoster ophthalmicus (HZO) as associated with corneal innervation. Design Prospective, controlled and masked cross-sectional study. Methods SETTING: Single-center study. PATIENTS: Thirty eyes with the diagnosis HZO and their contralateral clinically unaffected eyes, 15 eyes of 15 normal controls. INTERVENTION PROCEDURES: In vivo confocal microscopy and corneal esthesiometry of the central cornea. MAIN OUTCOME MEASURES: Changes in morphology and density of the superficial and basal epithelial cells and stromal keratocytes, and correlation with corneal sensation. Results The density of superficial epithelial cells in HZO eyes with severe sensation loss (766.5 ± 25.2 cells/mm2) was significantly lower than both healthy control eyes (1450.23 ± 150.83 cells/mm2) and contralateral unaffected eyes (1974.13 ± 298.24 cells/mm2) (P = .003). Superficial epithelial cell size (1162.5 μm2) was significantly larger in HZO eyes with severe loss of sensation, as compared to contralateral (441.46 ± 298.14) or healthy eyes (407.4 ± 47.2mm2; all P < .05). The density of basal epithelial cells, anterior keratocytes, and posterior keratocytes did not show statistical significance between patients, controls, and contralateral unaffected eyes. Changes in superficial epithelial cell density and morphology correlated strongly with corneal sensation. Conclusions In vivo confocal microscopy reveals profound HZO-induced changes in the superficial epithelium, as demonstrated by increase in cell size, decrease in cell density, and squamous metaplasia. We demonstrate that these changes strongly correlate with changes in corneal innervation in eyes affected by HZO.

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A Novel Mouse Model for Neurotrophic Keratopathy: Trigeminal Nerve Stereotactic Electrolysis through the Brain

Cited by 71 publications

References 41 publications

Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea

Intraepithelial dendritic cells and sensory nerves are structurally associated and functional interdependent in the cornea

Reduced intraepithelial corneal nerve density and sensitivity accompany desiccating stress and aging in C57BL/6 mice

In Vivo Confocal Microscopic Changes of the Corneal Epithelium and Stroma in Patients With Herpes Zoster Ophthalmicus

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