Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo

Ziming Luo; Kun-Che Chang; Suqian Wu; Catalina Sun; Xin Xia; Michael Nahmou; Minjuan Bian; Rain R Wen; Ying Zhu; Sahil Shah; Bogdan Tanasa; Marius Wernig; Jeffrey L Goldberg

doi:10.1016/j.stemcr.2022.10.011

Directly induced human retinal ganglion cells mimic fetal RGCs and are neuroprotective after transplantation in vivo

Stem Cell Reports. 2022 Dec 13;17(12):2690-2703. doi: 10.1016/j.stemcr.2022.10.011. Epub 2022 Nov 10.

Authors

Affiliations

¹ Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
² Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Department of Ophthalmology and Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
³ Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA; Shanghai Key Laboratory of Visual Impairment and Restoration, Department of Ophthalmology and Vision Science, Eye, Ear, Nose & Throat Hospital, Fudan University, Shanghai 200031, China.
⁴ Department of Pathology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA.
⁵ Spencer Center for Vision Research, Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA 94304, USA. Electronic address: luozm@stanford.edu.

Abstract

Retinal ganglion cell (RGC) replacement therapy could restore vision in glaucoma and other optic neuropathies. We developed a rapid protocol for directly induced RGC (iRGC) differentiation from human stem cells, leveraging overexpression of NGN2. Neuronal morphology and neurite growth were observed within 1 week of induction; characteristic RGC-specific gene expression confirmed identity. Calcium imaging demonstrated γ-aminobutyric acid (GABA)-induced excitation characteristic of immature RGCs. Single-cell RNA sequencing showed more similarities between iRGCs and early-stage fetal human RGCs than retinal organoid-derived RGCs. Intravitreally transplanted iRGCs survived and migrated into host retinas independent of prior optic nerve trauma, but iRGCs protected host RGCs from neurodegeneration. These data demonstrate rapid iRGC generation in vitro into an immature cell with high similarity to human fetal RGCs and capacity for retinal integration after transplantation and neuroprotective function after optic nerve injury. The simplicity of this system may benefit translational studies on human RGCs.

Keywords: induced retinal ganglion cell; neuroprotective; stem cell; transplant.

Publication types

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

MeSH terms

Glaucoma*
Humans
Optic Nerve Injuries* / metabolism
Retina
Retinal Ganglion Cells
Stem Cells

Abstract

Publication types

MeSH terms

Grants and funding