Establishment of vascularized human retinal organoids from induced pluripotent stem cells
Satoshi Inagaki, Shinsuke Nakamura, Yoshiki Kuse, Kota Aoshima, Michinori Funato, Masamitsu Shimazawa, Hideaki Hara
Abstract
Pluripotent 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, we generate the vascularized retinal organoids (vROs) from healthy human induced pluripotent stem cells. vROs are created from ROs by co-culturing them with vascular organoid (VO)-derived vascular endothelial cells/pericytes. The expression of mature neuronal markers is markedly higher in the vROs than in the ROs. When vROs are cultured under diabetic conditions, their size and the number of retinal ganglion cells are significantly decreased. In conclusion, the co-culture of ROs with VO-derived cells enables the production of ROs with vascular-like structures, and the vROs respond 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.