Hopx(+) optic nerve head-astrocytes counter neuronal stress and glaucoma damage

Bernstein, Steven L., Mehrabian, Zara, Guo, Yan, Jouffroy, Jean, Mead, Ben ORCID: https://orcid.org/0000-0001-5855-0097, Tomarev, Stanislav, Durmaz, Esmahan, Epstein, Jonathan A., Kronk, Adam, Blackshaw, Seth and Hoang, Thanh 2026. Hopx(+) optic nerve head-astrocytes counter neuronal stress and glaucoma damage. Proceedings of the National Academy of Sciences 123 (18) , e2515277123. 10.1073/pnas.2515277123

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Abstract

Retinal ganglion cell (RGC) axons form the optic nerve (ON). Numerous age-related ON diseases, including glaucoma, the second most common cause of worldwide blindness, result from multiple RGC stressors. Nearly all ON astrocytes in the optic nerve head (ONH): the junctional region between the ON and the retina in young-adult rodents expresses the homeodomain only (Hopx) protein. Hopx(+) ONH astrocytes are depleted during aging. ONH primary cultures which include Hopx(+) astrocytes secrete extracellular vesicles (ONH-EVs) which selectively enhance RGC survival and neurite extension in culture, while extracellular vesicles (EVs) secreted from distal ON cultures lacking Hopx(+) astrocytes do not. ONH-EVs also enhance RGC survival in vivo in a rodent model of glaucoma. Combining rat ONH single-cell (scRNA-seq) sequencing with EV proteomic analysis, we identified ONH-Hopx(+) astrocyte secreted factors. We interrogated the online Broad institute scRNA-seq database for rat RGC gene expression in control animals and following rodent ON crush, an RGC stress model, to correlate ONH-astrocyte secreted factors with RGC gene expression changes. Following stress, RGCs upregulate the complementary pathways involving Hopx(+) astrocytic-associated factors, suggesting reciprocal communication. Using a highly selective transgenic Hopx-cre ONH knockdown strategy, we demonstrate that eliminating Hopx(+) astrocytes also results in upregulation of RGC stress responses. Our results implicate age-related loss of young ONH-astrocytes as a crucial factor in the development of age-related optic nerve diseases, and discuss replacing ONH associated factors as a paradigm shift for ON disease treatment.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Optometry and Vision Sciences
Publisher:	National Academy of Sciences
ISSN:	0027-8424
Date of First Compliant Deposit:	18 May 2026
Date of Acceptance:	22 February 2026
Last Modified:	18 May 2026 10:15
URI:	https://orca.cardiff.ac.uk/id/eprint/187042

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