Single-cell transcriptome analysis of regenerating RGCs reveals potent glaucoma neural repair genes

Liang Li; Fang Fang; Xue Feng; Pei Zhuang; Haoliang Huang; Pingting Liu; Liang Liu; Adam Z Xu; Lei S Qi; Le Cong; Yang Hu

doi:10.1016/j.neuron.2022.06.022

Single-cell transcriptome analysis of regenerating RGCs reveals potent glaucoma neural repair genes

Neuron. 2022 Aug 17;110(16):2646-2663.e6. doi: 10.1016/j.neuron.2022.06.022. Epub 2022 Aug 10.

Authors

Liang Li¹, Fang Fang², Xue Feng¹, Pei Zhuang¹, Haoliang Huang¹, Pingting Liu¹, Liang Liu¹, Adam Z Xu³, Lei S Qi⁴, Le Cong⁵, Yang Hu⁶

Affiliations

¹ Spencer Center for Vision Research, Department of Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA 94304, USA.
² Spencer Center for Vision Research, Department of Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA 94304, USA; Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha 410011, China.
³ Saratoga High School, Saratoga, CA 95070, USA.
⁴ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H Institute, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neuroscience Institute, Stanford University, Stanford, CA 94305, USA.
⁶ Spencer Center for Vision Research, Department of Ophthalmology, Byers Eye Institute at Stanford University School of Medicine, Palo Alto, CA 94304, USA. Electronic address: huyang@stanford.edu.

Abstract

Axon regeneration holds great promise for neural repair of CNS axonopathies, including glaucoma. Pten deletion in retinal ganglion cells (RGCs) promotes potent optic nerve regeneration, but only a small population of Pten-null RGCs are actually regenerating RGCs (regRGCs); most surviving RGCs (surRGCs) remain non-regenerative. Here, we developed a strategy to specifically label and purify regRGCs and surRGCs, respectively, from the same Pten-deletion mice after optic nerve crush, in which they differ only in their regeneration capability. Smart-Seq2 single-cell transcriptome analysis revealed novel regeneration-associated genes that significantly promote axon regeneration. The most potent of these, Anxa2, acts synergistically with its ligand tPA in Pten-deletion-induced axon regeneration. Anxa2, its downstream effector ILK, and Mpp1 dramatically protect RGC somata and axons and preserve visual function in a clinically relevant model of glaucoma, demonstrating the exciting potential of this innovative strategy to identify novel effective neural repair candidates.

Keywords: Anxa2; ILK; Mpp1; Pten; RGC; Smart-Seq2; axon regeneration; glaucoma; neural repair; optic nerve.

Publication types

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

MeSH terms

Animals
Axons / physiology
Gene Expression Profiling
Glaucoma* / genetics
Mice
Nerve Regeneration / genetics
Optic Nerve Injuries* / genetics
Retinal Ganglion Cells / physiology

Abstract

Publication types

MeSH terms

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