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Mimicking Ocular Development and Treating Corneal Blindness using iPSCs

Review of “Co-ordinated ocular development from human iPS cells and recovery of corneal function” from Nature by Stuart P. Atkinson

We have made great leaps forward in our efforts to produce specific cell types from pluripotent stem cells (PSCs) for uses including drug testing, disease modelling, and cell replacement therapy. However, many studies focus on one cell type grown in two dimensional growth surfaces which may not recapitulate the in vivo setting adequately. This has led to an explosion of so-called “organoid” studies, where cells differentiate in three-dimensions forming a miniature organ-like complex structure. 

This, however, has remained difficult in tissues which rely on the involvement of tissues derived from multiple primordial cell lineages, such as in the eye. In an exciting advance, researchers from the laboratory of Kohji Nishida (Osaka University Graduate School of Medicine, Japan) now report on their new strategy to generate what they term a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. Formed from human induced pluripotent stem cells (iPSCs), the authors show how the SEAM mimics whole-eye development and, furthermore, how specific cells derived from the SEAM can treat an animal model of corneal blindness [1].

The overall differentiation of iPSCs followed a multi-stage long-term procedure (see the original study for a real eye full!), but started with the spontaneous formation of a structure with multiple concentric zones (the SEAM), much like an onion. Each of the 4 zones contained cells with a specific morphology and marker expression profile; zone 1 represented the neuroectoderm, zone 2 represented the neuro-retina, neural crest, and RPE, zone 3 represented the ocular surface epithelium, and zone 4 represented the general surface ectodermal cells. The study notes that this provides evidence that the SEAM formed mirrors whole eye development from the front of the ocular surface back to the retina.

So can we take advantage of this system to generate therapeutically relevant cells for transplantation? To answer this question, the study aimed to form corneal epithelium through isolation of ocular surface lineage cells from zone 3 of the SEAM. A thorough analysis revealed cells with characteristics of corneal, limbal, and conjunctival epithelial cells. Importantly, cells also had the ability to form expanded sheets with expression patterns and a gross morphology similar to the epithelium at the limbus of donated research human corneas. 

Excitingly, transplantation of these iPSC-derived sheets onto the eyes of a rabbit model of corneal epithelial stem-cell deficiency led to the formation of a healthy corneal barrier and the continued expression of cornea-specific proteins, suggesting their application as a therapeutic option for surgical repair for the front of the eye.

While surgical repair of the ocular surface has previously employed somatic stem cells, long-term results have not been overly encouraging [2-4]. So could iPSC-derived SEAM formation provide us with a new, efficient, and effective treatment option? The authors hope that an answer to this question will come from human clinical trials, driven and directed by these encouraging animal studies.


  1. Hayashi R, Ishikawa Y, Sasamoto Y, et al. Co-ordinated ocular development from human iPS cells and recovery of corneal function. Nature 2016;531:376-380.
  2. Nishida K, Yamato M, Hayashida Y, et al. Functional bioengineered corneal epithelial sheet grafts from corneal stem cells expanded ex vivo on a temperature-responsive cell culture surface. Transplantation 2004;77:379-385.
  3. Pellegrini G, Traverso CE, Franzi AT, et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 1997;349:990-993.
  4. Nakamura T, Inatomi T, Sotozono C, et al. Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. Br J Ophthalmol 2004;88:1280-1284.