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
Affiliations
Mengya Zhao
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA
Kenichi Toma
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA
Benyam Kinde
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding author
Liang Li
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Amit K. Patel
Viterbi Family Department of Ophthalmology, University of California San Diego, San Diego, CA 92037, USA
Kong-Yan Wu
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA
Matthew R. Lum
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA
Chengxi Tan
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA
Jody E. Hooper
Department of Pathology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Arnold R. Kriegstein
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
Anna La Torre
Department of Cell Biology and Human Anatomy, University of California, Davis, Davis, CA 95616, USA
Yaping Joyce Liao
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Derek S. Welsbie
Viterbi Family Department of Ophthalmology, University of California San Diego, San Diego, CA 92037, USA
Yang Hu
Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Corresponding author
Ying Han
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding author
Xin Duan
Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94158, USA; Corresponding author
Summary: 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.
