Generation of Multiple Ocular Lineages from Human Pluripotent Stem Cells and Its Application to Regenerative Medicine

Abstract

The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and corneal stroma have a neural crest origin. Recent work with pluripotent stem cells (PSCs) in culture has revealed a previously under-appreciated level of intrinsic cellular self-organization, with a focus on the retina and retinal cells. We recently demonstrated the generation from human induced pluripotent stem cells (iPSCs) of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. The concentric SEAM mimics whole-eye development because cell location within different zones is indicative of ocular cell lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. Therefore, SEAM represents a promising resource for new research of ocular morphogenesis and development. Moreover, we successfully isolated corneal epithelial progenitor cells and fabricated corneal epithelial tissue from PSCs. This approach has translational potential for treating severe corneal epithelial disease by transplantation of PSC-derived corneal epithelial tissue. To evaluate the efficacy and safety of the corneal epithelial tissue, we have started a first-in-human clinical study for patients with corneal epithelial stem cell deficiency, which began last year.