Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors

Cell Rep. 2021 Apr 20;35(3):109022. doi: 10.1016/j.celrep.2021.109022.

Abstract

Age-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.

Keywords: cell therapy; cone photoreceptor; degeneration; electrophysiology; macular degeneration; outer segment; rescue; retinal organoid; transplantation; visual function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation
  • Dependovirus / genetics
  • Dependovirus / metabolism
  • Disease Models, Animal
  • Gene Expression
  • Genetic Vectors / chemistry
  • Genetic Vectors / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Macular Degeneration / genetics
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Macular Degeneration / therapy*
  • Male
  • Mice
  • Mice, Transgenic
  • Mycotoxins / genetics
  • Mycotoxins / metabolism
  • Organoids / cytology
  • Organoids / metabolism
  • Organoids / transplantation*
  • Peripherins / genetics
  • Peripherins / metabolism
  • Photic Stimulation
  • Primary Cell Culture
  • Protein Kinase C-alpha / genetics
  • Protein Kinase C-alpha / metabolism
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism
  • Recovery of Function / physiology*
  • Retinal Bipolar Cells / cytology
  • Retinal Bipolar Cells / metabolism
  • Retinal Cone Photoreceptor Cells / cytology
  • Retinal Cone Photoreceptor Cells / metabolism*
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / metabolism
  • Synapses / metabolism
  • Transplantation, Heterologous
  • Vision, Ocular / physiology

Substances

  • Biomarkers
  • Mycotoxins
  • Peripherins
  • Prph2 protein, mouse
  • Receptors, Glutamate
  • phomopsin
  • Prkca protein, mouse
  • Protein Kinase C-alpha