A treatment within sight: challenges in the development of stem cell-derived photoreceptor therapies for retinal degenerative diseases

Abstract

Stem cell therapies can potentially treat various retinal degenerative diseases, including age-related macular degeneration (AMD) and inherited retinal diseases like retinitis pigmentosa. For these diseases, transplanted cells may include stem cell-derived retinal pigmented epithelial (RPE) cells, photoreceptors, or a combination of both. Although stem cell-derived RPE cells have progressed to human clinical trials, therapies using photoreceptors and other retinal cell types are lagging. In this review, we discuss the potential use of human pluripotent stem cell (hPSC)-derived photoreceptors for the treatment of retinal degeneration and highlight the progress and challenges for their efficient production and clinical application in regenerative medicine.

Keywords: cell therapy; human pluripotent stem cells; photoreceptors; regenerative medicine; retinal degeneration; retinal organoids.

Figure 1

Schematic diagrams of retinas from healthy and diseased eyes. The healthy retina shows the major cells of the retina, with a clear distinction between the photoreceptors of the macula vs. the peripheral retina. Age-related Macular Degeneration: Retinal schematic of the macula, as shown by the presence of cone photoreceptors. Intermediate (Int) AMD—The presence of sub-RPE drusen deposits and early signs of RPE dysfunction. Advanced (Adv) AMD—loss of RPE cells and cones in the macula. Retinitis Pigmentosa: Retinal schematic showing the progressive degeneration of rods in the peripheral retina. Intermediate (Int) RP—partial loss of rod. Advanced (Adv) RP—widespread loss of rods in the peripheral retina.

Figure 2

A schematic showing the source of human pluripotent stem cells from either a blastocyst-stage embryo or through hIPSC cell induction by reprogramming factors. hPSCs are then directed toward the eye field progenitor cells (EFPCs) by inhibition of TGFβ, BMP and WNT signalling Progression of differentiation to the RPE is governed by WNT signalling and is enhanced through inhibition of FGF signalling. Conversely, the differentiation of EFPCs towards neural retinal progenitor cells (NRPCs) is driven by FGF signalling and inhibition of WNT signalling. NRPCs have the differentiation potential to form all cells of the neural retina and can be cultured in suspension as 3D aggregates to form retinal organoids or under 2D conditions under directed differentiation towards rod or cone photoreceptors. Blue boxes show markers for each cell type.

Figure 3

(A) Major variations in the physical formats for retinal organoid and photoreceptor differentiation, showing combinations of 3D, 2D/3D, 3D/2D/3D and 2D culture systems. These approaches form the basis of derived and adapted protocols for the generation of retinal organoids and enhanced photoreceptor differentiation. (B) A heat map of the most utilized pathways during guided neural induction and early-to-mid retinal differentiation. Pathway activation or inhibition is commonly achieved using small molecules and exogenous cytokines. Adaptations of protocols are commonly explored by using additional specific molecules to enhance or promote target cell types, including photoreceptors.