Comparative Biology of Vertebrate Retinal Regeneration: Restoration of Vision through Cellular Reprogramming

Abstract

The regenerative capacity of the vertebrate retina varies substantially across species. Whereas fish and amphibians can regenerate functional retina, mammals do not. In this perspective piece, we outline the various strategies nonmammalian vertebrates use to achieve functional regeneration of vision. We review key differences underlying the regenerative potential across species including the cellular source of postnatal progenitors, the diversity of cell fates regenerated, and the level of functional vision that can be achieved. Finally, we provide an outlook on the field of engineering the mammalian retina to replace neurons lost to injury or disease.

Figure 1.

Basic anatomy of the vertebrate eye and retina. (A) The key parts of the eye are identified. The ciliary marginal zone [CMZ] is at the interface between the ciliary body and the retina (yellow). (B) The neural retina and retinal pigmented epithelium (RPE) are shown at higher magnification. The cell bodies of both rods and cones are in the outer nuclear layer [ONL] (blue and red). The inner nuclear layer (INL) contains the cell bodies of horizontal cells (dark blue), bipolar cells (purple), and amacrine cells (green). The retinal ganglion cells (RGCs) have their cell bodies in the innermost layer of the retina (yellow). Created using BioRender.com.

Figure 2.

Retinal regeneration in amphibian. (A) In response to complete removal of the retina, salamanders and tadpoles are able to mount a complete regenerative response. In a cartoon of the retina, ganglion cells (yellow), amacrine cells (pink), bipolar cells (brown), horizontal cells (purple), rods (blue), and cones (magenta) are depicted. (B) Retinal pigmented epithelium (RPE) are the primary cellular source for regeneration in amphibians and respond to injury by dedifferentiating and proliferating as neurogenic progenitors. (C) An entire functional retina can be regenerated by amphibian RPE. (D–F) Representative image of newt RPE (RPE65, red) reentering the cell cycle as progenitors (PCNA, green) in response to retinectomy. (F) Example of RPE-derived retinal regeneration in the newt using RPE65-CreERT2/floxed mCherry-based lineage tracing. (ONL) Outer nuclear layer, (OPL) outer plexiform layer, (INL) inner nuclear layer, (IPL) inner plexiform layer, (GCL) ganglion cell layer. (Panel D is reproduced from the Supplemental movie in Islam et al. 2014, courtesy of a Creative Commons Attribution 4.0 International License. Panels E and F are reprinted from Casco-Robles et al. 2016, courtesy of a Creative Commons Attribution 4.0 International License.) Additional figures created using BioRender.com.

Figure 3.

Retinal regeneration in fish. (A) Retinal injury stimulated by ganglion cell death (NMDA), photoreceptor death (light damage), or a broad neurotoxin (oubain) all lead to Müller glia (MG)-mediated regeneration. Cartoon depicts ganglion cells (yellow), bipolar cells (dark purple), amacrine cells (green), horizontal cells (blue), rods (light purple), and cones (brown). (B) In response to various modes of injury, MG reenter the cell cycle to produce multipotent progenitors. (C) MG-derived progenitors are capable of generating all classes of retinal neurons. (D) Example of lineage-traced MG reentering the cell cycle (BrdU⁺) and (E) up-regulating the proneural transcription factor Ascl1. (Panel E from Wan et al. 2012; reprinted, with permission, from Elsevier © 2012.) (F) Circuitry analysis of regenerated bipolars (xfz43⁺) shows reestablishment of connections with red, green, and ultraviolet (UV) cones. (Panel F from D'Orazi et al. 2016; reprinted, with permission, from Elsevier © 2012.) Additional figures created using BioRender.com.

Figure 4.

Retinal regeneration in chick. (A) NMDA injury that ablates retinal ganglion cells (yellow) and amacrine cells (green) stimulates a regenerative response in posthatch chick retina. (B) In response to damage chick Müller glia (MG) (pink) robustly proliferate and (C) a small portion of these proliferating MG differentiate into amacrine cells (brown). (D) Example of MG (Sox2⁺) proliferating (BrdU⁺) after retinal damage. (Panel D is reprinted from Todd et al. 2016a, courtesy of a Creative Commons Attribution 4.0 International License.) (E) Proliferating chick MG up-regulate progenitor genes like Ascl1 (Cash1). (ONL) Outer nuclear layer, (INL) inner nuclear layer, (IPL) inner plexiform layer, (GCL) ganglion cell layer. Scale bar, 50 μm. (Panel E from Fischer and Reh 2001; reprinted, with permission, from Elsevier © 2001.) (F) Representative image of a regenerated Brdu⁺ MG-derived HuC/D⁺ amacrine cell in damaged chick retina. (Panel F is reprinted from Todd et al. 2016a under the terms of the Creative Commons CC BY license.) Additional figures created using BioRender.com.

Figure 5.

Retinal regeneration in mouse. (A) In the normal mouse retina, Müller glia (MG) respond to retinal damage by undergoing an inflammatory processed called “gliosis.” Cartoon depicts ganglion cells (yellow), bipolar cells (dark purple), amacrine cells (green), horizontal cells (blue), rods (light purple), cones (brown), and MG (orange). (B) The combination of MG-specific Ascl1 overexpression, retinal injury, and trichostatin-A (TSA) treatment leads to MG-mediated regeneration of bipolar and amacrine neurons in the adult mouse retina. (C) Example of MG-derived (GFP⁺) bipolar neurons (CABP5⁺) that were regenerated through proliferating MG (EdU⁺). (D) Patch-clamp electrophysiology recordings have shown that MG-derived neurons can respond to light, suggesting circuit integration. (E) Single-cell RNA-seq analysis of MG-mediated regeneration show transitional states between MG, MG progenitors, and MG-derived neurons. (Panels C–E from Jorstad et al. 2020; reprinted, with permission, from Elsevier © 2020.) Additional figures created using BioRender.com.