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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

Lookup NU author(s): Dr Carla Mellough, Joseph Collin, Mahmoud Khazim, Dr Kathryn White, Professor Evelyne Sernagor, David Steel, Professor Majlinda Lako

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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 modelling.


Publication metadata

Author(s): Mellough CB, Collin J, Khazim M, White K, Sernagor E, Steel DH, Lako M

Publication type: Article

Publication status: Published

Journal: Stem Cells

Year: 2015

Volume: 33

Issue: 8

Pages: 2416-2430

Print publication date: 01/08/2015

Online publication date: 13/05/2015

Acceptance date: 11/03/2015

Date deposited: 28/01/2016

ISSN (electronic): 1549-4918

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1002/stem.2023

DOI: 10.1002/stem.2023


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