Resolving Neurodevelopmental and Vision Disorders Using Organoid Single-Cell Multi-omics

Abstract

Human organoid models of the central nervous system, including the neural retina, are providing unprecedented opportunities to explore human neurodevelopment and neurodegeneration in controlled culture environments. In this perspective, we discuss how the single-cell multi-omic toolkit has been used to identify features and limitations of brain and retina organoids, and how these tools can be deployed to study congenital brain malformations and vision disorders in organoids. We also address how to improve brain and retina organoid protocols to revolutionize in vitro disease modeling.

A single-cell guide to retinal development: Cell fate decisions of multipotent retinal progenitors in scRNA-seq

“…Human retinal organoids have emerged as an accessible and manipulatable system for studying retinal development and associated diseases (reviewed in Bell et al, 2020 ). To establish the authenticity of the organoid system, many studies have tested the extent to which retinal organoid development recapitulates human retinal development, including characterization of cell type composition and global changes in temporal gene expression ( Brancati et al, 2020 ; Collin et al, 2018 ; Cowan et al, 2020 ; Kallman et al, 2020 ; Kim et al, 2019 ; Lu et al, 2020 ; Sridhar et al, 2020 ). To begin to understand the developmental basis of retinal disease, researchers have examined the expression profiles of inherited retinal disease-associated genes across organoid cell types and developmental stages, beginning to elucidate mechanisms by which altered gene function/expression may contribute to disease pathologies ( Cowan et al, 2020 ).…”

Müller glia fused with adult stem cells undergo neural differentiation in human retinal models

“… 76 Thus, organoids open a broad number of possibilities – that could be combined with the newest technologies, such as single-cell sequencing or single-cell multi-omics – to, for example, study neural development and the origin of visual disorders. 77 We utilized growing organoids as a host tissue for engrafting hybrids as a mean to study the hybrids’ interactions within a living tissue and their differentiation potential. We propose a new use for human retinal organoids as a model for stem cell-based retinal regeneration.…”

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

“…However, the power of single-cell approaches is well exploited in the study of the tri-dimensional (3D) context, both of native organs and 3D neural cultures [ 90 , 91 ]. Indeed, although the 2D human-specific cultures were and are widely used and helped gain knowledge of human brain development, they have limitations in recapitulating the complexity of the structure and the cellular diversity of the brain, thus losing information regarding spatial architecture, cell to cell interactions, and neuronal connectivity.…”