Differentiation and Transplantation of Embryonic Stem Cell-Derived Cone Photoreceptors into a Mouse Model of End-Stage Retinal Degeneration

Stem Cell Reports. 2017 Jun 6;8(6):1659-1674. doi: 10.1016/j.stemcr.2017.04.030. Epub 2017 May 25.

Abstract

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.

Keywords: blindness; cell- and tissue-based therapy; mouse embryonic stem cells; retina; retinal cone photoreceptor cells; retinal degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Aipl1 protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Eye Proteins
  • Hepatocyte Nuclear Factor 6
  • Leukemia Inhibitory Factor
  • Nr2e3 protein, mouse
  • Nrl protein, mouse
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • Onecut1 protein, mouse
  • Opsins
  • Orphan Nuclear Receptors
  • Otx Transcription Factors
  • Otx2 protein, mouse
  • RNA, Small Interfering
  • Receptors, Notch
  • Tretinoin