Cell transplantation strategies for retinal repair

Abstract

Cell transplantation is a novel therapeutic strategy to restore visual responses to the degenerate adult neural retina and represents an exciting area of regenerative neurotherapy. So far, it has been shown that transplanted postmitotic photoreceptor precursors are able to functionally integrate into the adult mouse neural retina. In this review, we discuss the differentiation of photoreceptor cells from both adult and embryonic-derived stem cells and their potential for retinal cell transplantation. We also discuss the strategies used to overcome barriers present in the degenerate neural retina and improve retinal cell integration. Finally, we consider the future translation of retinal cell therapy as a therapeutic strategy to treat retinal degeneration.

Fig. 1

The mammalian retina. (a) A schematic diagram illustrating the layers of the mammalian retina (green rod and purple cone photoreceptors; red Müller cells and RPE; blue nuclei). (b) A schematic diagram illustrating the position of the various cell types present in the adult neural retina. These cells are subdivided into (i) the principal retinal circuit, (ii) the association neurons, and (iii) the neuroglia. (c) A sagittal retinal section from an Nrl.gfp (green; rod photoreceptors) mouse. Scale bar, 200 μm. (d) A single fluorescence image of an adult Nrl.gfp retinal section stained for CRALBP (red), a protein present in Müller cells and the RPE. Scale bar, 40 μm. (e) A single fluorescence image of a degenerating retinal section stained for CRALBP (red), demonstrating the disorganization and loss of photoreceptor cells (Nrl.gfp; green). Scale bar, 40 μm. Nuclei were counterstained with Hoechst 33342 (blue). CB, ciliary body; ON, optic nerve; ILM, inner limiting membrane; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OLM, outer limiting membrane; RPE, retinal pigment epithelium. (See Color Plate 1.1 in color plate section.)

Fig. 2

Photoreceptor precursor cell transplantation into the adult eye. (a) A schematic diagram of a mouse eye illustrating the subretinal transplantation of Nrl.gfp precursor cells (green) and the resulting cell mass (inserts). (b) A confocal image of integrated Nrl.gfp rod photoreceptors, 21 days after transplantation to an adult recipient. (c) A Nomarski confocal image of integrated Nrl.gfp rod photoreceptors. (d) A schematic representation of the structure of a rod photoreceptor. Nuclei were counterstained with Hoechst 33342 (blue). Scale bars, 20 μm. INL, inner nuclear layer; ONL, outer nuclear layer. (See Color Plate 1.2 in color plate section.)

Fig. 3

A summary of retinal cell transplantation strategies. A diagram to summarize the various retinal cell transplantation strategies and the related barriers that may limit transplanted photoreceptor cell integration in the adult and degenerate neural retina, as discussed in the main text. The donor cell population (top; green) can be derived from a variety of cell sources, but must be differentiated to the correct ontogenetic stage (postmitotic rod precursors, Nrl.gfp; green) prior to transplantation to enable photoreceptor cell integration into the host adult retina (MacLaren et al., 2006). The recipient retinal microenvironment (middle; blue) may also limit photoreceptor cell integration if the relevant barriers are not modulated at the time of transplantation. Scale bar, 50 μm. The relevant barriers to retinal cell transplantation and integration (right; red) are indicated. The outer limiting membrane (indicated by the red or black arrow head) forms a barrier to increased cell integration in the adult retina and in some models of retinal degeneration. Scale bars, 10 μm and 5 μm. Other barriers, present predominantly in the degenerate retina, include retinal cell death and the resulting activated microglia/macrophages and reactive gliosis/glial scarring. Scale bars, 50, 100, and 20 μm, respectively. Nuclei were counterstained with Hoechst 33342 (blue). ES cells, embryonic stem cells; GS, glutamine synthetase; MS cells, Müller stem-like cells; RS cells, retinal stem-like cells; ZO-1, zonula occludens-1. (See Color Plate 1.3 in color plate section.)