Establishment of Immunodeficient Retinal Degeneration Model Mice and Functional Maturation of Human ESC-Derived Retinal Sheets after Transplantation

Abstract

Summary: Increasing demand for clinical retinal degeneration therapies featuring human ESC/iPSC-derived retinal tissue and cells warrants proof-of-concept studies. Here, we established two mouse models of end-stage retinal degeneration with immunodeficiency, NOG-rd1-2J and NOG-rd10, and characterized disease progress and immunodeficient status. We also transplanted human ESC-derived retinal sheets into NOG-rd1-2J and confirmed their long-term survival and maturation of the structured graft photoreceptor layer, without rejection or tumorigenesis. We recorded light responses from the host ganglion cells using a multi-electrode array system; this result was consistent with whole-mount immunostaining suggestive of host-graft synapse formation at the responding sites. This study demonstrates an application of our mouse models and provides a proof of concept for the clinical use of human ESC-derived retinal sheets. : In this article, Mandai and colleagues developed the immune-deficient mouse lines with end-stage retinal degeneration and tested in them the functional maturation of human ESC-derived retinal tissues after transplantation. Light-responsive activities in the host retinal ganglion cells were detected in the transplanted area, which suggests functional potency of these graft tissues. Keywords: retinal regeneration, photoreceptor transplantation, human ESC, retinal degeneration, multiple electrode array