Graft-derived horizontal cells contribute to host-graft synapses in degenerated retinas after retinal organoid transplantation.

Stem cell-derived retinal organoid (RO) transplantation is a promising approach for treating retinal degenerative diseases such as retinitis pigmentosa. Photoreceptors (PRs) in RO sheets form synaptic connections with host bipolar cells (BCs) and improve visual function in animal models of advanced retinal degeneration. However, the contribution of horizontal cells (HCs), which are critical for PR synapse formation in the developing retina, to host-graft synapse formation remains unclear. In this study, we used HC-depleted retinal degeneration mice (rd1) and Islet1(-/-) genome-edited ROs (gROs) that contain HCs but not rod BCs and showed that host HC deficiency did not alter the number of host BC-graft PR synapses after transplantation into rd1, while the restored light sensitivity was enhanced in the context of host HCs. These findings indicate that graft-derived HCs alone can support host-graft synapse formation, whereas the presence of host HCs facilitates functional recovery after gRO transplantation.