Letter | Published:

Co-ordinated ocular development from human iPS cells and recovery of corneal function

Nature volume 531, pages 376380 (17 March 2016) | Download Citation


The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina, for example, develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and collagen-rich stroma of the cornea have a neural crest origin. Recent work with pluripotent stem cells in culture has revealed a previously under-appreciated level of intrinsic cellular self-organization, with a focus on the retina and retinal cells1,2,3,4,5. Moreover, we and others have demonstrated the in vitro induction of a corneal epithelial cell phenotype from pluripotent stem cells6,7,8,9. These studies, however, have a single, tissue-specific focus and fail to reflect the complexity of whole eye development. Here we demonstrate the generation from human induced pluripotent stem cells of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. In some respects the concentric SEAM mimics whole-eye development because cell location within different zones is indicative of lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. It thus represents a promising resource for new and ongoing studies of ocular morphogenesis. The approach also has translational potential and to illustrate this we show that cells isolated from the ocular surface ectodermal zone of the SEAM can be sorted and expanded ex vivo to form a corneal epithelium that recovers function in an experimentally induced animal model of corneal blindness.

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We thank K. Baba, Y. Oie, H. Takayanagi, S. Hara, Y. Yasukawa, J. Toga and M. Yagi of Osaka University and M. Nakagawa of Kyoto University for technical assistance and scientific discussions. This work was supported in part by the project for the realization of regenerative medicine of The Japan Agency for Medical Research and Development (AMED), The Japan Science and Technology Agency (JST) and The Ministry of Health, Labour, and Welfare of Japan and the Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

    • Ryuhei Hayashi
  2. Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

    • Ryuhei Hayashi
    • , Yuki Ishikawa
    • , Yuzuru Sasamoto
    • , Ryosuke Katori
    • , Naoki Nomura
    • , Tatsuya Ichikawa
    • , Saori Araki
    • , Takeshi Soma
    • , Satoshi Kawasaki
    • , Motokazu Tsujikawa
    •  & Kohji Nishida
  3. Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan

    • Kiyotoshi Sekiguchi
  4. Structural Biophysics Group, School of Optometry and Vision Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF24 4HQ, UK

    • Andrew J. Quantock


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R.H., M.T. and K.N. designed the research; R.H, Y.I., R.K. and S.A. performed the in vitro experiments and acquired the data; Y.S., N.N., T.I. and T.S. performed animal experiments and acquired the data; K.S. provided reagents (LN511E8); R.H., Y.I. and R.K. analysed the data and wrote the respective methods and results; S.K., K.S. and A.J.Q. supervised the project; and R.H., M.T., A.J.Q. and K.N. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kohji Nishida.

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    Supplementary Information

    This file contains Supplementary Tables 1-3.


  1. 1.

    Differentiating hiPSCs forming a SEAM

    A hiPSC colony shown throughout the first 25 days of culture in differentiation medium spontaneously generating a concentric SEAM and its multiple cellular zones.

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