Modeling Neurological Disorders in 3D Organoids Using Human-Derived Pluripotent Stem Cells

Abstract

Modeling neurological disorders is challenging because they often have both endogenous and exogenous causes. Brain organoids consist of three-dimensional (3D) self-organizing brain tissue which increasingly is being used to model various aspects of brain development and disorders, such as the generation of neurons, neuronal migration, and functional networks. These organoids have been recognized as important in vitro tools to model developmental features of the brain, including neurological disorders, which can provide insights into the molecular mechanisms involved in those disorders. In this review, we describe recent advances in the generation of two-dimensional (2D), 3D, and blood-brain barrier models that were derived from induced pluripotent stem cells (iPSCs) and we discuss their advantages and limitations in modeling diseases, as well as explore the development of a vascularized and functional 3D model of brain processes. This review also examines the applications of brain organoids for modeling major neurodegenerative diseases and neurodevelopmental disorders.

Keywords: blood-brain barrier; hiPSCs; neural organoids; neurological disorders; vascularization.

Figure 1

Comparison of 2D and 3D cell culture models and their limitations. Although 3D models overcome some of the limitations of 2D models, the generation of new 3D models is needed to increase vascularization, cellular diversity, viability, and reproducibility as well as a more accurate recapitulation of disease phenotypes. EBs, embryoid bodies; Neu, Neuron; Astro, astrocytes; Oligo, oligodendrocyte; mGlia, microglia; BMECs, brain microvascular endothelial cells; Pericyt, pericyte.