iPSC-Derived Retina Transplants Improve Vision in rd1 End-Stage Retinal-Degeneration Mice

Abstract

SummaryRecent success in functional recovery by photoreceptor precursor transplantation in dysfunctional retina has led to an increased interest in using embryonic stem cell (ESC) or induced pluripotent stem cell (iPSC)-derived retinal progenitors to treat retinal degeneration. However, cell-based therapies for end-stage degenerative retinas that have lost the outer nuclear layer (ONL) are still a big challenge. In the present study, by transplanting mouse iPSC-derived retinal tissue (miPSC retina) in the end-stage retinal-degeneration model (rd1), we visualized the direct contact between host bipolar cell terminals and the presynaptic terminal of graft photoreceptors by gene labeling, showed light-responsive behaviors in transplanted rd1 mice, and recorded responses from the host retina with transplants by ex vivo micro-electroretinography and ganglion cell recordings using a multiple-electrode array system. Our data provides a proof of concept for transplanting ESC/iPSC retinas to restore vision in end-stage retinal degeneration.

Assessment of Safety and Functional Efficacy of Stem Cell-Based Therapeutic Approaches Using Retinal Degenerative Animal Models

“…Other investigations suggested that success of RPC transplantation is achieved through trophic factor release rather than direct replacement of the lost cells [ 59 , 66 – 68 ]. A major challenge in incorporating photoreceptors and other neuronal cell types is the establishment of synaptic connections with the proximal neuronal elements of the recipient retina [ 2 , 69 – 71 ]. Using transsynaptic tracing techniques and donor cell label, synaptic connections between fetal retinal sheet transplants and the host retina have been previously reported [ 72 – 74 ].…”

Reproducibility and staging of 3D human retinal organoids across multiple pluripotent stem cell lines

“…The capacity to generate bona fide fetal-stage neural retinal cell types and tissues from human embryonic and induced pluripotent stem cells (hESCs and hiPSCs; collectively, hPSCs) has spurred their use in disease modeling (Tucker et al, 2011(Tucker et al, , 2013Jin et al, 2012;Phillips et al, 2014;Yoshida et al, 2015;Arno et al, 2016;Parfitt et al, 2016;Megaw et al, 2017;Schwarz et al, 2017;Sharma et al, 2017;Shimada et al, 2017;Deng et al, 2018) and photoreceptor (PR) replacement efforts (Lamba et al, 2009(Lamba et al, , 2010Hambright et al, 2012;Barnea-Cramer et al, 2016;Shirai et al, 2016;Chao et al, 2017;Gonzalez-Cordero et al, 2017;Mandai et al, 2017;Zhu et al, 2017Zhu et al, , 2018Iraha et al, 2018;Lakowski et al, 2018;McLelland et al, 2018;Gagliardi et al, 2018). Most of these studies employ hPSC differentiation methods that propagate retinal progeny as isolated 3D optic vesicle-like structures (OVs), also known as retinal organoids, in suspension culture (Meyer et al, 2009(Meyer et al, , 2011Nakano et al, 2012;Phillips et al, 2012Phillips et al, , 2018bSridhar et al, 2016;Reichman et al, 2014;Zhong et al, 2014;Kuwahara et al, 2015;Mellough et al, 2015;Singh et al, 2015;Lowe et al, 2016;…”

Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: A pluripotent stem cell-based approach

“…Ex vivo multielectrode array (MEA) recordings demonstrated that light-responsive signals were transmitted to bipolar cells and then to host RGCs in the grafted area, although the measured amplitudes were smaller than those of wild-type retina and displayed more variable patterns. The optokinetic test failed to show a visual improvement in transplanted animals over dystrophic controls, while light-responsive behavior, analyzed through an adaptation of a shuttle-avoidance system in mice pre-selected to have substantial amount of subretinal grafts, were detected in around half of the tested animals (Mandai et al, 2017a). This proof-of-concept study showed that iPSC-derived retinal sheets can developed a mature ONL when transplanted into the subretinal space of end-stage retinal-degeneration mice and can respond to light.…”

“…However, these rosettes often had INL-like layer surrounding the ONL, blocking the contact with host RPE on the other side (Assawachananont et al, 2014). Aiming at visualizing a direct host-graft synaptic contact, the same group generated a specific mouse reporter iPSC line to derive retinal sheets that express CtBP2-tdTomato at photoreceptor synaptic terminals (Nrl-GFP/ROSA::Nrl-CtBP2-tdTomato) after differentiation (Mandai et al, 2017a). To identify rod bipolar cells, the authors generated L7-GFP/rd1 mice, by crossing rd1 mice with L7-GFP mice that express GFP in rod bipolar cells.…”

“…Retinal sheet transplants could lead to some functional restoration (Mandai et al, 2017a;McLelland et al, 2018;Shirai et al, 2016); nevertheless, the presence of retinal cell types other than photoreceptors, as well as the assembling into neural rosettes reduces the ability of transplanted retinal cells to reconnect within the host tissue and restore the visual function. On the contrary, transplantation of cell suspensions, if appropriately selected, can lead to a homogenous population of photoreceptors, although only a fraction of these cells can survive after the injection (Gagliardi et al, 2018).…”