Differential effects of Hsp90 inhibition on corneal cells in vitro and in vivo

Raghunathan, Vijay Krishna; Edwards, Sydney; Leonard, Brian C.; Kim, Soohyun; Evashenk, Alexander T.; Song, Yeonju; Rewinski, Eva; Price, Ariana Marangakis; Hoehn, Alyssa L.; Chang, Connor; Reilly, Christopher M.; Muppala, Santoshi; Murphy, Christopher J.; Thomasy, Sara M

doi:10.1016/j.exer.2020.108362

Cited by 7 publications

(6 citation statements)

References 81 publications

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“…Administration of recombinant Hsp90α protein can accelerate the healing process of burn injuries in mice. 34 , 38 We show here that the administration of recombinant Hsp90α can promote wound healing after mechanical injury of the cornea. However, it is unclear whether eHsp90α utilizes the same pathways to facilitate recovery after different mechanisms of injury.…”

Section: Discussionmentioning

confidence: 68%

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The Therapeutic Roles of Recombinant Hsp90α on Cornea Epithelial Injury

Wang

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to explore the therapeutic role of heat shock protein 90 (Hsp90) in wound healing of injury cornea epithelium. Methods The right eye of C57BL/6N male mice were performed the debridement wounds in the center of the cornea using an algerbrush II blade. The injured area was determined by staining the cornea with fluorescein sodium and measured with image-J. Immunoblotting, ELISA and immunochemistry were used for determining protein expression. The quantitation PCR was performed to measure mRNA expression. Results Hsp90α is upregulated at both the mRNA and protein levels, and is secreted extracellularly into the corneal stroma and tear film during the healing process after corneal injury in mice. This upregulation is associated with activation of HSF1. Administration of recombinant exogenous Hsp90α (eHsp90α) speeds up wound healing of injured corneal epithelium. The eHsp90α binds to low-density lipoprotein (LDL)-related protein-1 (LRP-1) on the corneal epithelial cells and increases phosphorylation of AKT at S473, which is associated with proliferation and migration corneal epithelial cells in vitro or vivo. Inhibition of AKT by its inhibitor LY294002 abolishes eHsp90α-induced migration and proliferation of corneal epithelial cells. Conclusions Hsp90α is upregulated and secreted after corneal injury and acts to promote the healing process. Recombinant Hsp90α may be a promising therapeutic drug candidate for corneal injury.

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Section: Discussionmentioning

confidence: 68%

“… 33 After injury, Hsp90 is upregulated in corneal stroma keratinocytes and works with TGF-β1 to modulate the transition from keratinocytes to myofibroblast. 34 However, the role of eHsp90α during corneal wound healing still remains unclear.…”

mentioning

confidence: 99%

The Therapeutic Roles of Recombinant Hsp90α on Cornea Epithelial Injury

Wang

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…We previously showed that Hsp90 inhibition with 17AAG promoted reversion of the myofibroblast to keratocyte phenotype ( Fig. 13 ), in the presence or absence of TGFβ1, on rigid substrates in vitro ( Raghunathan et al, 2021 ). However, rabbits treated with 17AAG developed greater stromal haze formation and αSMA positive myofibroblasts compared with controls, irrespective of frequency of administration.…”

Section: Stromamentioning

confidence: 87%

Squishy matters – Corneal mechanobiology in health and disease

Thomasy,

Leonard,

Greiner

et al. 2024

Progress in Retinal and Eye Research

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“…Stromal haze thickness as reflected by a hyperreflective zone in the OCT image was measured manually using the caliper function integrated into the OCT software as described previously. 40 Fluorescein stain (HUB Pharmaceuticals, LLC, Rancho Cucamonga, CA) was performed to assess epithelial wound area twice daily with digital photography (Nikon D300). The remaining wound area at each time point was measured using ImageJ software (version 1.52k) and compared with the baseline wound area for each rabbit, and the percentage of the remaining wound area was calculated for each time point.…”

Section: Methodsmentioning

confidence: 99%

Metal Oxide Engineered Nanomaterials Modulate Rabbit Corneal Fibroblast to Myofibroblast Transformation

Fukuto

Kim

Kang

et al. 2021

Trans. Vis. Sci. Tech.

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Purpose Corneal keratocyte-fibroblast-myofibroblast (KFM) transformation plays a critical role in corneal stromal wound healing. However, the impact of engineered nanomaterials (ENMs), found in an increasing number of commercial products, on this process is poorly studied. This study investigates the effects of metal oxide ENMs on KFM transformation in vitro and in vivo. Methods Cell viability of rabbit corneal fibroblasts (RCFs) was tested following treatment with 11 metal oxide ENMs at concentrations of 0.5 to 250 µg/ml for 24 hours. Messenger RNA (mRNA) and protein expression of αSMA, a marker of myofibroblast transformation, were measured using RCFs after exposure to 11 metal oxide ENMs at a concentration that did not affect cell viability, in media containing either 0 or 10 ng/ml of TGF-β1. Additionally, the effect of topical Fe 2 O 3 nanoparticles (NPs) (50 ng/ml) on corneal stromal wound healing following phototherapeutic keratectomy (PTK) was determined. Results V 2 O 5 , Fe 2 O 3 , CuO, and ZnO ENMs were found to significantly reduce cell viability as compared to vehicle control and the other seven metal oxide ENMs tested. V 2 O 5 nanoflakes significantly reduced mRNA and protein αSMA concentrations in the presence of TGF-β1. Fe 2 O 3 NPs significantly increased αSMA mRNA expression in the presence of TGF-β1 but did not alter αSMA protein expression. Topically applied Fe 2 O 3 NPs in an in vivo rabbit corneal stromal wound healing model did not delay healing. Conclusions Fe 2 O 3 NPs promote corneal myofibroblast induction in vitro but do not impair corneal stromal wound healing in vivo. Translational Relevance These experimental results can apply to human nanomedical research.

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Differential effects of Hsp90 inhibition on corneal cells in vitro and in vivo

Cited by 7 publications

References 81 publications

The Therapeutic Roles of Recombinant Hsp90α on Cornea Epithelial Injury

The Therapeutic Roles of Recombinant Hsp90α on Cornea Epithelial Injury

Squishy matters – Corneal mechanobiology in health and disease

Metal Oxide Engineered Nanomaterials Modulate Rabbit Corneal Fibroblast to Myofibroblast Transformation

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