title: IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells.
abstract: We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells under defined culture conditions. While both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process, and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three-dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signaling significantly reduces the formation of optic vesicle and optic cups, while exogenous IGF-1 treatment enhances the formation of correctly laminated retinal tissue composed of multiple retinal phenotypes that is reminiscent of the developing vertebrate retina. Most importantly, hESC-derived photoreceptors exhibit advanced maturation features such as the presence of primitive rod- and cone-like photoreceptor inner and outer segments and phototransduction-related functional responses as early as 6.5 weeks of differentiation, making these derivatives promising candidates for cell replacement studies and in vitro disease modeling.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Carla B
authors.initials: CB
authors.lastname: Mellough
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Collin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.|Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Khazim
authors.affiliation: EM Research Services, Newcastle University, Newcastle, United Kingdom.
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle, United Kingdom.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Sernagor
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.|Sunderland Eye Infirmary, Sunderland, United Kingdom.
authors.forename: David H W
authors.initials: DH
authors.lastname: Steel
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
authors.forename: Majlinda
authors.initials: M
authors.lastname: Lako
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C583557:IGF1 protein, human; D007334:Insulin-Like Growth Factor I
keywords: Differentiation; Human pluripotent stem cells; IGF-1; Neural retina; Retinal pigmented epithelium
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