Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment§

Authors

  • Jason S. Meyer,

    Corresponding author
    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    • Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Telephone: 317-274-1040; Fax: 317-274-2846

  • Sara E. Howden,

    1. Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin, USA
    2. The Genome Center of Wisconsin, University of Wisconsin, Madison, Wisconsin, USA
    3. Morgridge Institute for Research, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Kyle A. Wallace,

    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Amelia D. Verhoeven,

    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Lynda S. Wright,

    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Elizabeth E. Capowski,

    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Isabel Pinilla,

    1. Department of Ophthalmology, Blesa University Hospital and the Instituto Aragones de Ciencias de la Salud, Zaragoza, Spain
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Jessica M. Martin,

    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Shulan Tian,

    1. Morgridge Institute for Research, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Ron Stewart,

    1. Morgridge Institute for Research, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Bikash Pattnaik,

    1. Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA
    2. Department of Pediatrics, and University of Wisconsin, Madison, Wisconsin, USA
    3. Eye Research Institute, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • James A. Thomson,

    1. Department of Cell and Regenerative Biology, University of Wisconsin, Madison, Wisconsin, USA
    2. The Genome Center of Wisconsin, University of Wisconsin, Madison, Wisconsin, USA
    3. Morgridge Institute for Research, Madison, Wisconsin, USA
    4. Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • David M. Gamm

    Corresponding author
    1. Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    2. Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, USA
    3. Eye Research Institute, University of Wisconsin, Madison, Wisconsin, USA
    • Waisman Center, University of Wisconsin, Madison, Wisconsin, USA
    Search for more papers by this author
    • Author contributions: J.S.M. and S.E.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; K.A.W.: collection and/or assembly of data, data analysis and interpretation; A.D.V., I.P., and J.M.M.: collection and/or assembly of data; L.S.W.: data analysis and interpretation, manuscript writing; E.E.C.: conception and design, data analysis and interpretation; S.T.: collection and/or assembly of data, data analysis and interpretation, manuscript writing; R.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; B.P.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.T.: conception and design, financial support, data analysis and interpretation, final approval of manuscript; D.M.G.: conception and design, financial support, data analysis and interpretation, manuscript writing, final approval of manuscript.

    • Telephone: 608-261-1516; Fax: 608-890-3479


  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS June 15, 2011.

Abstract

Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine. STEM CELLS 2011;29:1206-1218

Ancillary