Transplantation of human iPSC-derived retinal cells in the cone-dominant Northern tree shrew

Abstract: Purpose: To characterize the transplantation and survival of photoreceptors generated from human induced pluripotent stem cell (hiPSC)-derived retinal organoids in the Northern tree shrew (Tupaia belangeri, TS). Methods: TS eyes were injected with retinal cells dissociated from GFP-expressing hiPSC-derived retinal organoids (12 animals; n=22 eyes). 15 eyes had prior damage induced by either experimental retinal detachment (n=11) or ATP-induced retinal damage (n=4), and seven eyes were undamaged. Retinal organoids were treated with Notch pathway inhibitor 2 days before transplant. TS retinal structure and cellular details were assessed post-transplantation for up to 8 weeks using scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and adaptive optics SLO (AOSLO). Histological analysis was done at the end of the experiment. Results: Cell transplants in eyes treated with a simple immunosuppression treatment failed to survive for more than 2 weeks (n=10 eyes). Robust cell survival was observed in the eyes treated with a complex immunosuppression cocktail for up to 8 weeks (n=12 eyes). The transplanted cells were confirmed to be subretinally located using OCT imaging and the cell fate was confirmed to be human photoreceptors by histology. Finally, AOSLO imaging captured structures resembling photoreceptor inner segments. Conclusions: Our results demonstrate survival of transplanted cells using a species-specific immunosuppression treatment. Future studies should aim to explore the long-term survival and function of the transplanted cells.