Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration
Copyright policy )Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration
The loss of cone photoreceptors that mediate daylight vision represents a leading cause of blindness, for which cell replacement by transplantation offers a promising treatment strategy. Here, we characterize cone differentiation in retinas derived from mouse embryonic stem cells (mESCs). Similar to in vivo development, a temporal pattern of progenitor marker expression is followed by the differentiation of early thyroid hormone receptor β2-positive precursors and, subsequently, photoreceptors exhibiting cone-specific phototransduction-related proteins. We establish that stage-specific inhibition of the Notch pathway increases cone cell differentiation, while retinoic acid signaling regulates cone maturation, comparable with their actions in vivo. MESC-derived cones can be isolated in large numbers and transplanted into adult mouse eyes, showing capacity to survive and mature in the subretinal space of Aipl1-/- mice, a model of end-stage retinal degeneration. Together, this work identifies a robust, renewable cell source for cone replacement by purified cell suspension transplantation.
- King's College London United Kingdom
- University College London United Kingdom
- Kings College London, University of London United Kingdom
- University of Lausanne Switzerland
- UNIVERSITY COLLEGE LONDON, Bartlett School of Planning United Kingdom
ROD PHOTORECEPTORS, retina, Medicine (General), mouse embryonic stem cells, DEVELOPMENTAL EXPRESSION, Leukemia Inhibitory Factor, cell- and tissue-based therapy, Mice, Biology (General), RNA, Small Interfering, PRECURSORS, Mice, Knockout, Otx Transcription Factors, Receptors, Notch, Retinal Degeneration, THYROID-HORMONE RECEPTOR, Cell Differentiation, Mouse Embryonic Stem Cells, Orphan Nuclear Receptors, REPLACEMENT, Hepatocyte Nuclear Factor 6, Basic-Leucine Zipper Transcription Factors, Retinal Cone Photoreceptor Cells, RNA Interference, Life Sciences & Biomedicine, Signal Transduction, blindness, 570, QH301-705.5, FATE, 610, Tretinoin, MAMMALIAN RETINA, Article, R5-920, Cell & Tissue Engineering, Animals, Eye Proteins, RESTORATION, Adaptor Proteins, Signal Transducing, Science & Technology, Opsins, Cell Biology, Oligodendrocyte Transcription Factor 2, retinal cone photoreceptor cells, MICE, Disease Models, Animal, Adaptor Proteins, Signal Transducing/deficiency; Adaptor Proteins, Signal Transducing/genetics; Animals; Basic-Leucine Zipper Transcription Factors/antagonists & inhibitors; Basic-Leucine Zipper Transcription Factors/genetics; Basic-Leucine Zipper Transcription Factors/metabolism; Cell Differentiation/drug effects; Disease Models, Animal; Eye Proteins/antagonists & inhibitors; Eye Proteins/genetics; Eye Proteins/metabolism; Hepatocyte Nuclear Factor 6/metabolism; Leukemia Inhibitory Factor/pharmacology; Mice; Mice, Knockout; Mouse Embryonic Stem Cells/cytology; Mouse Embryonic Stem Cells/transplantation; Oligodendrocyte Transcription Factor 2/metabolism; Opsins/metabolism; Orphan Nuclear Receptors/antagonists & inhibitors; Orphan Nuclear Receptors/genetics; Orphan Nuclear Receptors/metabolism; Otx Transcription Factors/metabolism; RNA Interference; RNA, Small Interfering/metabolism; Receptors, Notch/antagonists & inhibitors; Receptors, Notch/metabolism; Retinal Cone Photoreceptor Cells/cytology; Retinal Cone Photoreceptor Cells/metabolism; Retinal Degeneration/pathology; Retinal Degeneration/therapy; Signal Transduction; Tretinoin/metabolism; Tretinoin/pharmacology; blindness; cell- and tissue-based therapy; mouse embryonic stem cells; retina; retinal cone photoreceptor cells; retinal degeneration, PROGENITOR CELLS, retinal degeneration
ROD PHOTORECEPTORS, retina, Medicine (General), mouse embryonic stem cells, DEVELOPMENTAL EXPRESSION, Leukemia Inhibitory Factor, cell- and tissue-based therapy, Mice, Biology (General), RNA, Small Interfering, PRECURSORS, Mice, Knockout, Otx Transcription Factors, Receptors, Notch, Retinal Degeneration, THYROID-HORMONE RECEPTOR, Cell Differentiation, Mouse Embryonic Stem Cells, Orphan Nuclear Receptors, REPLACEMENT, Hepatocyte Nuclear Factor 6, Basic-Leucine Zipper Transcription Factors, Retinal Cone Photoreceptor Cells, RNA Interference, Life Sciences & Biomedicine, Signal Transduction, blindness, 570, QH301-705.5, FATE, 610, Tretinoin, MAMMALIAN RETINA, Article, R5-920, Cell & Tissue Engineering, Animals, Eye Proteins, RESTORATION, Adaptor Proteins, Signal Transducing, Science & Technology, Opsins, Cell Biology, Oligodendrocyte Transcription Factor 2, retinal cone photoreceptor cells, MICE, Disease Models, Animal, Adaptor Proteins, Signal Transducing/deficiency; Adaptor Proteins, Signal Transducing/genetics; Animals; Basic-Leucine Zipper Transcription Factors/antagonists & inhibitors; Basic-Leucine Zipper Transcription Factors/genetics; Basic-Leucine Zipper Transcription Factors/metabolism; Cell Differentiation/drug effects; Disease Models, Animal; Eye Proteins/antagonists & inhibitors; Eye Proteins/genetics; Eye Proteins/metabolism; Hepatocyte Nuclear Factor 6/metabolism; Leukemia Inhibitory Factor/pharmacology; Mice; Mice, Knockout; Mouse Embryonic Stem Cells/cytology; Mouse Embryonic Stem Cells/transplantation; Oligodendrocyte Transcription Factor 2/metabolism; Opsins/metabolism; Orphan Nuclear Receptors/antagonists & inhibitors; Orphan Nuclear Receptors/genetics; Orphan Nuclear Receptors/metabolism; Otx Transcription Factors/metabolism; RNA Interference; RNA, Small Interfering/metabolism; Receptors, Notch/antagonists & inhibitors; Receptors, Notch/metabolism; Retinal Cone Photoreceptor Cells/cytology; Retinal Cone Photoreceptor Cells/metabolism; Retinal Degeneration/pathology; Retinal Degeneration/therapy; Signal Transduction; Tretinoin/metabolism; Tretinoin/pharmacology; blindness; cell- and tissue-based therapy; mouse embryonic stem cells; retina; retinal cone photoreceptor cells; retinal degeneration, PROGENITOR CELLS, retinal degeneration
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