Generation of retinal pigment epithelial cells from small molecules and OCT4 reprogrammed human induced pluripotent stem cells

Tim U. Krohne, Peter D. Westenskow, Toshihide Kurihara, David F. Friedlander, Mandy Lehmann, Alison L. Dorsey, Wenlin Li, Saiyong Zhu, Andrew Schultz, Junhua Wang, Gary Siuzdak, Sheng Ding, Martin Friedlander

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61 Citations (Scopus)

Abstract

Autologous retinal pigment epithelium (RPE) grafts derived from induced pluripotent stem cells (iPSCs) may be used to cure blinding diseases in which RPE dysfunction results in photoreceptor degeneration. Four-, two-, and one-factor-derived iPSCs (4F-, 2F-, and 1F-iPSCs, respectively) were differentiated into fully functional cuboidal pigmented cells in polarized monolayers that express RPE-specific markers. 1F-iPSC-RPE (1F-iPS-RPE) strongly resembles primary human fetal RPE (hfRPE) based on proteomic and untargeted metabolomic analyses, and using novel in vivo imaging technology coupled with electroretinography, we demonstrated that 1F-iPS-RPE mediate anatomical and functional rescue of photoreceptors after transplantation in an animal model of RPE-mediated retinal degeneration. 1F-iPS-RPE cells were injected subretinally as a suspension and formed a monolayer dispersed between host RPE cells. Furthermore, 1F-iPS-RPE do not simply provide trophic support to rescue photoreceptors as previously speculated but actually phagocytose photoreceptor outer segments in vivo and maintain visual cycling. Thus, 1F-iPS-RPE grafts may be superior to conventional iPS-RPE for clinical use because 1F-iPS-RPE closely resemble hfRPE, mediate anatomical and functional photoreceptor rescue in vivo, and are generated using a reduced number of potentially oncogenic reprogramming factors.

Original languageEnglish
Pages (from-to)96-109
Number of pages14
JournalStem Cells Translational Medicine
Volume1
Issue number2
DOIs
Publication statusPublished - 2012 Jan 1

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Keywords

  • Aging
  • Differentiation
  • Induced pluripotent stem cells
  • Retina
  • Small molecules
  • Stem cell transplantation

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

Cite this

Krohne, T. U., Westenskow, P. D., Kurihara, T., Friedlander, D. F., Lehmann, M., Dorsey, A. L., Li, W., Zhu, S., Schultz, A., Wang, J., Siuzdak, G., Ding, S., & Friedlander, M. (2012). Generation of retinal pigment epithelial cells from small molecules and OCT4 reprogrammed human induced pluripotent stem cells. Stem Cells Translational Medicine, 1(2), 96-109. https://doi.org/10.5966/sctm.2011-0057