Establishment of vascularized human retinal organoids from induced pluripotent stem cells.

Abstract

Stem cell-derived retinal organoids (ROs) have been investigated for applications in regenerative medicine, retinal disease models, and compound safety evaluation. Although the development of 3D organoids has provided novel opportunities for innovation, some unresolved limitations continue to exist in organoid research. The passive diffusion of oxygen and nutrients limits the growth and functional gain of organoids. Vascularization may circumvent these problems because it allows oxygen and nutrients to enter the organoid core. In the present study, ROs and vascular organoids (VOs) were generated from healthy human induced pluripotent stem cells. We attempted to create vascular-like structures in ROs by co-culturing them with VO-derived vascular endothelial cells/pericytes. Our vascularized retinal organoids (vROs) contained type IV collagen- and CD31-positive vascular-like structures. The expression of the mature neuronal marker SMI-32 and SNCG was markedly higher in the vROs than in the ROs. When vROs were cultured under conditions that mimicked diabetes, their size and the number of retinal ganglion cells were significantly decreased. In conclusion, the co-culture of ROs with VO-derived cells enabled the production of ROs with vascular-like structures, and the vROs responded to severe diabetic retinopathy conditions. In summary, our findings underscore the potential of vROs as invaluable tools for elucidating disease mechanisms and screening therapeutic interventions for retinal vascular disorders, thereby paving the way for personalized medicine approaches in ophthalmology.