Studies of Scleral Biomechanical Behavior Related to Susceptibility for Retinal Ganglion Cell Loss in Experimental Mouse Glaucoma

Nguyen, Cathy; Cone, Frances E.; Nguyen, Thao D.; Coudrillier, Baptiste; Pease, Mary Ellen; Steinhart, Matthew R.; Oglesby, Ericka; Jefferys, Joan L.; Quigley, Harry A.

doi:10.1167/iovs.12-10952

Cited by 87 publications

(102 citation statements)

References 70 publications

(89 reference statements)

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“…18,42 A growing body of research has shown that the sclera becomes stiffer in glaucoma. 7,43,44 These latter findings would support a link between myofibroblast-mediated detrimental sclera remodeling and mechanical damage to the ONH.…”

Section: Discussionmentioning

confidence: 75%

High-Magnitude and/or High-Frequency Mechanical Strain Promotes Peripapillary Scleral Myofibroblast Differentiation

Zhu

Ambalavanan

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To determine the effects of altered mechanical strain on human peripapillary scleral (ppSc) fibroblast-to-myofibroblast differentiation.METHODS. Eight human ppSc fibroblast cultures were isolated from three paired eyes and two unilateral eyes of five donors using an explant approach. Human ppSc fibroblast isolates were subjected to 1% and 4% cyclic strain at 0.05 to 5 Hz for 24 hours. Levels of a smooth muscle actin (aSMA) mRNA and protein were determined by real-time PCR and immunoblot. Incorporation of aSMA into actin stress fibers was evaluated by confocal immunofluorescent microscopy. Myofibroblast contractility was measured by fibroblast-populated three-dimensional collagen gel contraction assay and phosphorylation of myosin light chain (MLC 20 ).RESULTS. Human ppSc fibroblasts contained 6% to 47% fully differentiated myofibroblasts before strain application; 4% cyclic strain increased aSMA mRNA and protein expression in ppSc fibroblasts compared with 1% strain applied at 5 Hz, but not at lower frequencies. Seven of eight ppSc fibroblast isolates responded to high-magnitude and high-frequency strain with increased cellular contractility and increased MLC 20 phosphorylation. In addition, increasing strain frequency promoted aSMA expression in ppSc fibroblasts under both 1% and 4% strain conditions.CONCLUSIONS. High-magnitude and/or high-frequency mechanical strain promotes differentiation of human ppSc fibroblasts into contractile myofibroblasts, a fibroblast phenotypic change known to be key to tissue injury-repair responses. These findings suggest that the cellular constituent of ppSc may play an important role in the regulation of optic nerve head biomechanics in response to injurious IOP fluctuations.

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Section: Discussionmentioning

confidence: 75%

High-Magnitude and/or High-Frequency Mechanical Strain Promotes Peripapillary Scleral Myofibroblast Differentiation

Zhu

Ambalavanan

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…Interestingly, the two measures of scleral thickness change in opposite directions in glaucoma mice. Fresh PPS is significantly thinner after glaucoma, while the fixed sclera in epoxy sections is thicker Nguyen et al, 2013). This would suggest that nonfibrillar (water soluble) components of the scleral matrix decrease or at least lose their capacity to bind water (thinner fresh sclera), while there is a small but significant increase in fibrous components, chiefly collagen (thicker fixed sclera).…”

Section: Scleral and Onh Changes In Mouse Glaucomamentioning

confidence: 99%

The contribution of the sclera and lamina cribrosa to the pathogenesis of glaucoma

Quigley

2015

Progress in Brain Research

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“…8 Scleral thickness is greatest at the peripapillary zone, followed by the limbus, and is thinnest in midsclera. [9][10][11][12] The scleral collagen fibril diameter is larger 13 and varies more than in the cornea 14 or the lamina cribrosa of the ONH. 15 Scleral collagen fibrils, mostly type 1, are arranged in stacked and interwoven lamellae in which most fibrils course in parallel, with successive lamellae alternating in orientation.…”

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confidence: 99%

“…16 Aca23 mice (mice of B6 background that are homozygous for mutation in collagen 8a2) are significantly protected against injury from experimental glaucoma, 30,31 while CD1 mice are considerably more susceptible to damage than B6 mice 32 and differ in important features of scleral anatomy and response. 9,33 Experimental glaucoma in mice increases axial length and width by 6% to 10%, with thinning of the peripapillary sclera and increased scleral stiffness in mechanical inflation testing. Types of mice that are more resistant to glaucoma injury have stiffer sclera in mechanical testing at baseline, and with chronic IOP increase, they undergo less midscleral thinning and resist axial elongation better.…”

mentioning

confidence: 99%

“…Types of mice that are more resistant to glaucoma injury have stiffer sclera in mechanical testing at baseline, and with chronic IOP increase, they undergo less midscleral thinning and resist axial elongation better. 9,16 Recent experimental results suggest that an important change in mouse glaucomatous eyes is loss of the interfibrillar matrix as the eye elongates and stiffens. 16 While modeling of scleral biomechanical behavior has included parameters that stand in for the matrix, its actual features have not been studied in detail in glaucoma models.…”

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confidence: 99%

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Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

Pease

Oglesby

Cone-Kimball

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To determine differences in scleral permeability, as measured by diffusion of macromolecules, by using fluorescence recovery after photobleaching (FRAP), with reference to differences by mouse strain, scleral region, and the effect of experimental glaucoma.METHODS. In three mouse strains (B6, CD1, and B6 mice with mutation in collagen 8a2[Aca23]), we used FRAP to measure the diffusion of fluorescein isothiocyanate-dextran, molecular weight 40 kDa, into a photobleached zone of sclera. Scleral regions near the optic nerve head (peripapillary) and two successively more anterior regions were compared. Sclera from mouse eyes subjected to chronically elevated intraocular pressure after bead injection into the anterior chamber were compared to fellow eye controls. FRAP data were compared against estimated retinal ganglion cell axon loss in glaucomatous eyes.RESULTS. Diffusion rates of dextran molecules in the sclera were significantly greater in Aca23 and B6 mice than in CD1 mice in a multivariate model adjusted for region and axial length (P < 0.0001). Dextran diffusion significantly decreased in glaucomatous eyes, and the decline increased with greater axon loss (P ¼ 0.0003, multivariable model). Peripapillary scleral permeability was higher in CD1 than B6 and Aca23 mice (P < 0.05, multivariable model, adjusted by Bonferroni). CONCLUSIONS.Measurement of the diffusion rates of dextran molecules in the sclera showed that glaucoma leads to decreased scleral permeability in all three mouse strains tested. Among mouse strains tested, those that were more susceptible to glaucomatous loss of retinal ganglion cells had a lower scleral permeability at baseline.Keywords: glaucoma, mouse, experimental model, sclera, diffusion, permeability, photobleaching, dextran G laucoma is the second leading cause of world blindness and its principal risk factors include the effect of intraocular pressure (IOP) acting to decrease the number of retinal ganglion cells (RGCs). Intraocular pressure is a mechanical load that generates stress and strain in the sclera, which are magnified at the optic nerve head (ONH). The largest mechanical strains have been measured in in vitro inflation experiments in the peripapillary region, immediately adjacent to the ONH.1 The sclera acts on the ONH, where axons of RGCs pass out of the eye, and suffers damage related to the effects of IOP.2,3 Thus, the behavior of the sclera is highly relevant to glaucoma injury and its study may be useful in improved diagnosis as well as new therapeutic avenues.The sclera comprises three-quarters of the human ocular circumference and is 75% to 90% collagen, with additional elastin fibrils and proteoglycans. 4,5 The scleral proteoglycans include heparin sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronan, aggrecan, and several small leucinerich proteoglycans.6,7 These may have important functional significance for the mechanical responses of the sclera. 8 Scleral thickness is greatest at the peripapillary zone, followed by the limbus, and is...

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Studies of Scleral Biomechanical Behavior Related to Susceptibility for Retinal Ganglion Cell Loss in Experimental Mouse Glaucoma

Cited by 87 publications

References 70 publications

High-Magnitude and/or High-Frequency Mechanical Strain Promotes Peripapillary Scleral Myofibroblast Differentiation

High-Magnitude and/or High-Frequency Mechanical Strain Promotes Peripapillary Scleral Myofibroblast Differentiation

The contribution of the sclera and lamina cribrosa to the pathogenesis of glaucoma

Scleral Permeability Varies by Mouse Strain and Is Decreased by Chronic Experimental Glaucoma

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