Osteopontin drives retinal ganglion cell resiliency in glaucomatous optic neuropathy

Mengya Zhao; Kenichi Toma; Benyam Kinde; Liang Li; Amit K Patel; Kong-Yan Wu; Matthew R Lum; Chengxi Tan; Jody E Hooper; Arnold R Kriegstein; Anna La Torre; Yaping Joyce Liao; Derek S Welsbie; Yang Hu; Ying Han; Xin Duan

doi:10.1016/j.celrep.2023.113038

Osteopontin drives retinal ganglion cell resiliency in glaucomatous optic neuropathy

Cell Rep. 2023 Sep 26;42(9):113038. doi: 10.1016/j.celrep.2023.113038. Epub 2023 Aug 23.

Authors

Mengya Zhao¹, Kenichi Toma¹, Benyam Kinde², Liang Li³, Amit K Patel⁴, Kong-Yan Wu¹, Matthew R Lum¹, Chengxi Tan¹, Jody E Hooper⁵, Arnold R Kriegstein⁶, Anna La Torre⁷, Yaping Joyce Liao³, Derek S Welsbie⁴, Yang Hu⁸, Ying Han⁹, Xin Duan¹⁰

Affiliations

¹ Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA.
² Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: bkinde@gmail.com.
³ Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
⁴ Viterbi Family Department of Ophthalmology, University of California San Diego, San Diego, CA 92037, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
⁶ Department of Neurology and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA 95616, USA.
⁸ Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA. Electronic address: huyang@stanford.edu.
⁹ Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: ying.han@ucsf.edu.
¹⁰ Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA. Electronic address: xin.duan@ucsf.edu.

Abstract

Chronic neurodegeneration and acute injuries lead to neuron losses via diverse processes. We compared retinal ganglion cell (RGC) responses between chronic glaucomatous conditions and the acute injury model. Among major RGC subclasses, αRGCs and intrinsically photosensitive RGCs (ipRGCs) preferentially survive glaucomatous conditions, similar to findings in the retina subject to axotomy. Focusing on an αRGC intrinsic factor, Osteopontin (secreted phosphoprotein 1 [Spp1]), we found an ectopic neuronal expression of Osteopontin (Spp1) in other RGCs subject to glaucomatous conditions. This contrasted with the Spp1 downregulation subject to axotomy. αRGC-specific Spp1 elimination led to significant αRGC loss, diminishing their resiliency. Spp1 overexpression led to robust neuroprotection of susceptible RGC subclasses under glaucomatous conditions. In contrast, Spp1 overexpression did not significantly protect RGCs subject to axotomy. Additionally, SPP1 marked adult human RGC subsets with large somata and SPP1 expression in the aqueous humor correlated with glaucoma severity. Our study reveals Spp1's role in mediating neuronal resiliency in glaucoma.

Keywords: CP: Neuroscience; Osteopontin; glaucoma; human retina; neuronal types; neuroprotection; optic nerve crush; retinal ganglion cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Glaucoma*
Humans
Optic Nerve / metabolism
Optic Nerve Diseases* / metabolism
Osteopontin
Retinal Ganglion Cells / metabolism

Substances

Osteopontin

Abstract

Publication types

MeSH terms

Substances

Grants and funding