Abstract

We previously reported the differentiation of mouse embryonic stem (ES) cells into retinal progenitors. However, these progenitors rarely differentiate into photoreceptors unless they are cultured with embryonic retinal tissues. Here we show the in vitro generation of putative rod and cone photoreceptors from mouse, monkey and human ES cells by stepwise treatments under defined culture conditions, in the absence of retinal tissues. With mouse ES cells, Crx⁺ photoreceptor precursors were induced from Rx⁺ retinal progenitors by treatment with a Notch signal inhibitor. Further application of fibroblast growth factors, Shh, taurine and retinoic acid yielded a greater number of rhodopsin⁺ rod photoreceptors, in addition to default cone production. With monkey and human ES cells, feeder- and serum-free suspension culture combined with Wnt and Nodal inhibitors induced differentiation of Rx⁺ or Mitf⁺ retinal progenitors, which produced retinal pigment epithelial cells. Subsequent treatment with retinoic acid and taurine induced photoreceptor differentiation. These findings may facilitate the development of human ES cell–based transplantation therapies for retinal diseases.

1. Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
2. Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, 606-8507, Japan.
3. Organogenesis and Neurogenesis Group, Center for Developmental Biology, RIKEN, Kobe, 650-0047, Japan.
4. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan.
5. Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
6. Shiga Medical Center for Adults, Moriyama, 524-8524, Japan.
7. These authors contributed equally to this work.

Correspondence to: Masayo Takahashi^1,2 e-mail: mretina@cdb.riken.jp

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