title: Quantification of Retinogenesis in 3D Cultures Reveals Epigenetic Memory and Higher Efficiency in iPSCs Derived from Rod Photoreceptors.
abstract: Cell-based therapies to treat retinal degeneration are now being tested in clinical trials. However, it is not known whether the source of stem cells is important for the production of differentiated cells suitable for transplantation. To test this, we generated induced pluripotent stem cells (iPSCs) from murine rod photoreceptors (r-iPSCs) and scored their ability to make retinae by using a standardized quantitative protocol called STEM-RET. We discovered that r-iPSCs more efficiently produced differentiated retinae than did embryonic stem cells (ESCs) or fibroblast-derived iPSCs (f-iPSCs). Retinae derived from f-iPSCs had fewer amacrine cells and other inner nuclear layer cells. Integrated epigenetic analysis showed that DNA methylation contributes to the defects in f-iPSC retinogenesis and that rod-specific CTCF insulator protein-binding sites may promote r-iPSC retinogenesis. Together, our data suggest that the source of stem cells is important for producing retinal neurons in three-dimensional (3D) organ cultures.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hiler
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hazen
authors.affiliation: Mouse Genetics Core Facility, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kupriyanov
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Carroll
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Chunxu
authors.initials: C
authors.lastname: Qu
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Beisi
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Dianna
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Lyra
authors.initials: L
authors.lastname: Griffiths
authors.affiliation: Cell and Tissue Imaging Shared Resource, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.affiliation: Mouse Genetics Core Facility, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Alberto R
authors.initials: AR
authors.lastname: Rodriguez
authors.affiliation: Mouse Genetics Core Facility, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Greg
authors.initials: G
authors.lastname: Martin
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jiakun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jongrye
authors.initials: J
authors.lastname: Jeon
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98108, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
authors.affiliation: Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Baldwin
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Ophthalmology, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: michael.dyer@stjude.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Dyer
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation; D002460:Cell Line; D065150:Cellular Reprogramming; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D012160:Retina / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology / Q000628:therapy; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000378:metabolism*