Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs

Abstract

Many forms of blindness result from the dysfunction or loss of retinal photoreceptors. Induced pluripotent stem cells (iPSC) hold great potential for the modeling of these diseases or as potential therapeutic agents. However, to fulfill this promise, a remaining challenge is to induce human iPSC to recreate in vitro key structural and functional features of the native retina, in particular the presence of photoreceptors with outer-segment discs and light-sensitivity. Here we report that hiPSC can, in a highly autonomous manner, recapitulate spatiotemporally each of the main steps of retinal development observed in vivo and form 3-dimensional retinal cups that contain all major retinal cell types arranged in their proper layers. Moreover, the photoreceptors in our hiPSC-derived retinal tissue achieve advanced maturation, showing the beginning of outer-segment-disc formation and photosensitivity. This success brings us one step closer to the anticipated use of hiPSC for disease modeling and open possibilities for future therapies.

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

“…Sasai's discovery also provided a way to generate immature, but partially laminated, retina-like human tissue rather than PRs, resembling human embryonic retina, and use it for translational applications. Recently, several laboratories have demonstrated the ability of retinospheres to partially recapitulate retinal development [24][25][26] using this elegant 3D in vitro model.…”

“…Furthermore, some PRs responded to light, indicating that they had acquired functional properties in addition to expressing molecular markers of PRs [26]. In the current study, we tested whether inner retinal neurons in hESCderived retinal tissue have acquired functional characteristics in addition to expressing amacrine and RGC markers.…”

“…A recent study showed that retinal tissue derived from human iPSCs contained all five classes of neurons (rod/cone PRs, horizontal, bipolar, amacrine, and ganglion) as well as Müller glia and that these cells organized systematically into layers [26]. Furthermore, some PRs responded to light, indicating that they had acquired functional properties in addition to expressing molecular markers of PRs [26].…”

“…Recent reports demonstrated that hESCs and induced pluripotent stem cells (iPSCs) can generate optic vesicle-and optic cup-like structures and produce retinal progenitors that differentiate into RPE, PRs, inner nuclear layer (INL) neurons, and retinal ganglion cells (RGCs) [24][25][26]. Culturing hPSC-derived retinal spheres in suspension for up to 6 months demonstrated the ability of retinal organoids to form cell layers, including PRs with outer disklike protrusions and photosensitivity [26], which are challenging to purify in 2D monolayer culture [27]. However, the main advantage of deriving 3D tissue rather than PR progenitors is that the organization of embryonic-like tissue can be preserved.…”

Profile of King-Wai Yau

“…In addition to basic research, Yau has been engaged in translational work on ocular diseases in collaborations, such as with his close colleagues Jeremy Nathans (14) and Maria Canto Soler (15 …”