Astrocytes in the Optic Nerve Head of Glaucomatous Mice Display a Characteristic Reactive Phenotype

Wang, Rui; Seifert, Philip; Jakobs, Tatjana C.

doi:10.1167/iovs.16-20571

Cited by 74 publications

(66 citation statements)

References 62 publications

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“…With acute injury (nerve crush), astrocyte processes appear to detach from the edge [ 49 ], but this likely reflects the more severe nature of the injury. Similar to our results in the myelinated nerve, astrocyte remodeling following induced short-term elevations in pressure is most extensive distal from the sclera [ 55 ]. Portions of the optic nerve beyond the sclera itself are unlikely to be impacted directly by elevated IOP, and secondary changes could involve different structural mechanisms.…”

Section: Discussionsupporting

confidence: 89%

Astrocyte remodeling without gliosis precedes optic nerve axonopathy

Cooper

Collyer

Calkins

2018

acta neuropathol commun

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Astroyctes serve myriad functions but are especially critical in white matter tracts, where energy-demanding axons propagate action potentials great distances between neurons. Axonal dependence on astrocytes for even normal function accentuates the critical role astrocytes serve during disease. In glaucoma, the most common optic neuropathy, sensitivity to intraocular pressure (IOP) challenges RGC axons early, including degradation of anterograde transport to the superior colliculus (SC). Astrocyte remodeling presages overt axon degeneration in glaucoma and thus may present a therapeutic opportunity. Here we developed a novel metric to quantify organization of astrocyte processes in the optic nerve relative to axon degeneration in the DBA/2 J hereditary mouse model of glaucoma. In early progression, as axons expand prior to loss, astrocyte processes become more parallel with migration to the nerve’s edge without a change in overall coverage of the nerve. As axons degenerate, astrocyte parallelism diminishes with increased glial coverage and reinvasion of the nerve. In longitudinal sections through aged DBA/2 J nerve, increased astrocyte parallelism reflected elevated levels of the astrocyte gap-junction protein connexin 43 (Cx43). In the distal nerve, increased Cx43 also indicated with a higher level of intact anterograde transport from retina to SC. Our results suggest that progression of axonopathy in the optic nerve involves astrocyte remodeling in two phases. In an early phase, astrocyte processes organize in parallel, likely through gap-junction coupling, while a later phase involves deterioration of organization as glial coverage increases and axons are lost.

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Section: Discussionsupporting

confidence: 89%

Astrocyte remodeling without gliosis precedes optic nerve axonopathy

Cooper

Collyer

Calkins

2018

acta neuropathol commun

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“… 1 Although axonal loss is not present within 3 days in the bead injection model, actin reorganization may represent an initial result of IOP-produced strain. The increase in actin area in R1 could be due to the extension of new fine processes 17 to separate adjoining axons that were swelling, resulting in the increase in individual axonal compartments presented in this study.…”

Section: Discussionmentioning

confidence: 75%

“…Changes in astrocyte morphology in glaucoma models have been reported, primarily through immunolabeling of glial fibrillary acidic protein (GFAP), an intermediate filament component in astrocytes. Thickening and thinning of processes, 15 , 16 development of new processes along the ON axis, 17 and reorganization of filaments 18 have been shown after different time points of axonal insult. Tehrani et al 19 showed reorientation of actin-labelled rat astrocyte processes from a direction transverse to the ON axis to that along the ON axis.…”

mentioning

confidence: 98%

Pressure-Induced Changes in Astrocyte GFAP, Actin, and Nuclear Morphology in Mouse Optic Nerve

Ling

Pease

Jefferys

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose To conduct quantitative analysis of astrocytic glial fibrillary acidic protein (GFAP), actin and nuclei distribution in mouse optic nerve (ON) and investigate changes in the measured features after 3 days of ocular hypertension (OHT). Method Serial cross-sections of 3-day microbead-induced OHT and control ONs were fluorescently labelled and imaged using confocal microscope. Eighteen structural features were measured from the acquired images, including GFAP coverage, actin area fraction, process thickness, and aspect ratio of cell nucleus. The measured features were analyzed for variations with axial locations along ON and radial zones transverse to ON, as well as for the correlations with degree of intraocular pressure (IOP) change. Results The most significant changes in structural features after 3-day OHT occurred in the unmyelinated ON region (R1), and the changes were greater with greater IOP elevation. Although the GFAP, actin, axonal, and ON areas all increased in 3-day OHT ONs in R1 ( P ≤ 0.004 for all), the area fraction of GFAP actually decreased ( P = 0.02), the actin area fraction was stable and individual axon compartments were unchanged in size. Within R1, the number of nuclear clusters increased ( P < 0.001), but the mean size of nuclear clusters was smaller ( P = 0.02) and the clusters became rounder ( P < 0.001). In all cross-sections of control ONs, astrocytic processes were thickest in the rim zone compared with the central and peripheral zones ( P ≤ 0.002 for both), whereas the overall process width in R1 decreased after 3 days of OHT ( P < 0.001). Conclusions The changes in structure elucidated IOP-generated alterations that underlie astrocyte mechanotranslational responses relevant to glaucoma.

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“… 1 It is often considered that mechanical insult within the LC contributes to glaucomatous damage. 1 – 6 This may involve several paths, such as compression or shearing of the RGC axons potentially affecting axoplasmic transport, 3 , 7 stretch-induced activation of astrocytes, 8 – 13 or disruption of the vasculature and ischemia. 7 , 11 , 14 , 15 Overall, a larger mechanical insult is thought to translate into a higher likelihood of neural tissue damage.…”

mentioning

confidence: 99%

Thin Lamina Cribrosa Beams Have Different Collagen Microstructure Than Thick Beams

Brazile

Hua

Jan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeTo compare the collagen microstructural crimp characteristics between thin and thick lamina cribrosa (LC) beams.MethodsSeven eyes from four sheep were fixed at 5 mm Hg IOP in 10% formalin. For each eye, one to three coronal cryosections through the LC were imaged with polarized light microscopy and analyzed to visualize the LC and determine collagen fiber microstructure. For every beam, we measured its width and three characteristics of the crimp of its collagen fibers: waviness, tortuosity, and amplitude. Linear mixed effects models were used to test whether crimp characteristics were associated with the LC beam width.ResultsFor each eye and over all the eyes, LC beam width was positively associated with crimp waviness and tortuosity, and negatively associated with crimp amplitude (P's < 0.0001). Thin beams, average width 13.11 μm, had average (SD) waviness, tortuosity, and amplitude of 0.27 (0.17) radians, 1.017 (0.028) and 1.88 (1.41) μm, respectively. For thick beams, average width 26.10 μm, these characteristics were 0.33 (0.18) radians, 1.025 (0.037) and 1.58 (1.36) μm, respectively.ConclusionsOur results suggest heterogeneity in LC beam mechanical properties. Thin beams were less wavy than their thicker counterparts, suggesting that thin beams may stiffen at lower IOP than thick beams. This difference may allow thin beams to support similar amounts of IOP-induced force as thicker beams, thus providing a similar level of structural support to the axons at physiologic IOP, despite the differences in width. Measurements of beam-level mechanical properties are needed to confirm these predictions.

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Astrocytes in the Optic Nerve Head of Glaucomatous Mice Display a Characteristic Reactive Phenotype

Cited by 74 publications

References 62 publications

Astrocyte remodeling without gliosis precedes optic nerve axonopathy

Astrocyte remodeling without gliosis precedes optic nerve axonopathy

Pressure-Induced Changes in Astrocyte GFAP, Actin, and Nuclear Morphology in Mouse Optic Nerve

Thin Lamina Cribrosa Beams Have Different Collagen Microstructure Than Thick Beams

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