Unravelling the stromal-nerve interactions in the human diabetic cornea

Priyadarsini, Shrestha; Rowsey, Tyler; Xing, Jian; Karamichos, Dimitrios

doi:10.1016/j.exer.2017.08.003

Cited by 14 publications

(9 citation statements)

References 78 publications

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“…An obvious limitation of this work is that all experiments were performed in vitro and only evaluated the effects of hyperglycemia in the corneal epithelium. Both corneal nerves and corneal stromal cells have been shown to respond to changes in glucose and have impaired signaling in the diabetic cornea [52]. Future work should expand on the presented data to incorporate three-dimensional models and the in vivo condition.…”

Section: Discussionmentioning

confidence: 99%

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

et al. 2019

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Corneal wounds usually heal quickly; but diabetic patients have more fragile corneas and experience delayed and painful healing. In the present study, we compared the healing capacity of corneal epithelial cells (CECs) between normal and diabetic conditions and the potential mechanisms. Primary murine CEC derived from wild-type and diabetic (db/db) mice, as well as primary human CEC were prepared. Human CEC were exposed to high glucose (30 mM) to mimic diabetic conditions. Cell migration and proliferation were assessed using Scratch test and MTT assays, respectively. Reactive oxygen species (ROS) production in the cells was measured using dichlorofluorescein reagent. Western blot was used to evaluate the expression levels of Akt. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) expression were used to determine tight junction integrity. We found that the diabetic CEC displayed significantly slower cell proliferation and migration compared with the normal CEC from both mice and humans. Furthermore, ROS production was markedly increased in CEC grown under diabetic conditions. Treatment with an antioxidant N-acetyl cysteine (NAC, 100 μM) significantly decreased ROS production and increased wound healing in diabetic CEC. Barrier function was significantly reduced in both diabetic mouse and human CEC, while NAC treatment mitigated these effects. We further showed that Akt signaling was impaired in diabetic CEC, which was partially improved by NAC treatment. These results show that diabetic conditions lead to delayed wound-healing capacity of CEC and impaired tight junction formation in both mice and human. Increased ROS production and inhibited Akt signaling may contribute to this outcome, implicating these as potential targets for treating corneal wounds in diabetic patients.

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Section: Discussionmentioning

confidence: 99%

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

et al. 2019

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“…We have previously developed a 3D model of the human corneal stroma that relied upon self-assembly of an ECM produced by hCFs in situ over 4 weeks [16,17]. This 3D stromal model has been applied in the study of endothelial [30] and neuronal [41] cell interactions, as well as in investigations of the effects of hypoxia [42,43] and corneal disease (e.g., keratoconus [44] and diabetes [45]). In this study, we report the development and characterization of corneal epithelial-stromal co-cultures that are constructed using the 3D in vitro model with an overlaying epithelial layer.…”

Section: Discussionmentioning

confidence: 99%

Corneal Epithelial–Stromal Fibroblast Constructs to Study Cell–Cell Communication in Vitro

et al. 2019

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Cell–cell communication plays a fundamental role in mediating corneal wound healing following injury or infection. Depending on the severity of the wound, regeneration of the cornea and the propensity for scar development are influenced by the acute resolution of the pro-fibrotic response mediated by closure of the wound via cellular and tissue contraction. Damage of the corneal epithelium, basement membrane, and anterior stroma following a superficial keratectomy is known to lead to significant provisional matrix deposition, including secretion of fibronectin and thrombospondin-1, as well as development of a corneal scar. In addition, corneal wounding has previously been shown to promote release of extracellular vesicles from the corneal epithelium, which, in addition to soluble factors, may play a role in promoting tissue regeneration. In this study, we report the development and characterization of a co-culture system of human corneal epithelial cells and corneal stromal fibroblasts cultured for 4 weeks to allow extracellular matrix deposition and tissue maturation. The secretion of provisional matrix components, as well as small and large extracellular vesicles, was apparent within the constructs, suggesting cell–cell communication between epithelial and stromal cell populations. Laminin-1β was highly expressed by the corneal epithelial layer with the presence of notable patches of basement membrane identified by transmission electron microscopy. Interestingly, we identified expression of collagen type III, fibronectin, and thrombospondin-1 along the epithelial–stromal interface similar to observations seen in vivo following a keratectomy, as well as expression of the myofibroblast marker, α-smooth muscle actin, within the stroma. Our results suggest that this corneal epithelial–stromal model may be useful in the study of the biochemical phenomena that occur during corneal wound healing.

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“…NGF can stimulate regeneration of damaged neurons and mucin production by goblet cells 96. Topical NGF was shown to improve ocular surface integrity and corneal sensitivity in corneal neuropathy 97.…”

Section: Treatment Of Anterior Segment Complicationsmentioning

confidence: 99%

Influence of diabetes mellitus on anterior segment of the eye

Han

Yang

Hyon

2018

CIA

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Diabetes mellitus (DM) has been emerging as one of the most serious health problems worldwide. Ocular complications of DM are currently one of the major causes of blindness in developed countries, among which diabetic retinopathy is relatively well studied and understood. However, although ocular surface complications of DM are common, diabetic complications of anterior segment of the eye, such as, cornea, conjunctiva, and lacrimal glands, are often overlooked. DM is associated with progressive damage to corneal nerves and epithelial cells, which increases the risk of anterior segment disorders including dry eye disease, corneal erosion, persistent epithelial defects, and even sight-threatening corneal ulcer. In this review, the authors will discuss the association of DM with disorders of anterior segment of the eye. Studies indicating the value of corneal nerve assessment as a sensitive, noninvasive, and repeatable biomarker for diabetic neuropathy will also be introduced. In addition, treatment modalities of anterior segment disorders associated with DM is discussed. The studies introduced in this review suggest that early and periodic screening of the anterior segment of the eye, as well as the retina, is important for the optimal treatment of DM.

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Unravelling the stromal-nerve interactions in the human diabetic cornea

Cited by 14 publications

References 78 publications

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

Diabetes inhibits corneal epithelial cell migration and tight junction formation in mice and human via increasing ROS and impairing Akt signaling

Corneal Epithelial–Stromal Fibroblast Constructs to Study Cell–Cell Communication in Vitro

Influence of diabetes mellitus on anterior segment of the eye

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