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

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-iPSCs-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-iPS0RPE 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.

• Authors: 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
• Journal: Stem cells translational medicine (Stem Cells Transl Med) Vol. 1 Issue 2 Pg. 96-109 (Feb 2012) ISSN: 2157-6564 [Print] England
• PMID: 22532929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Culture Media, Conditioned
• Homeodomain Proteins
• NANOG protein, human
• Nanog Homeobox Protein
• Octamer Transcription Factor-3
• POU5F1 protein, human
• RNA, Messenger

Topics

• Animals
• Biomarkers (metabolism)
• Cell Culture Techniques
• Cell Differentiation
• Cells, Cultured
• Culture Media, Conditioned
• Electroretinography
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Immunohistochemistry
• Induced Pluripotent Stem Cells (cytology, metabolism)
• Keratinocytes (cytology, metabolism)
• Metabolomics
• Models, Animal
• Nanog Homeobox Protein
• Octamer Transcription Factor-3 (genetics, metabolism)
• Phagocytosis
• RNA, Messenger (genetics, metabolism)
• Rats
• Retinal Degeneration (metabolism, therapy)
• Retinal Photoreceptor Cell Outer Segment (metabolism, transplantation)
• Retinal Pigment Epithelium (cytology, metabolism)
• Swine (metabolism)