Utilizing hiPSC-derived oligodendrocytes to study myelin pathophysiology in neuropsychiatric and neurodegenerative disorders.

Abstract

Oligodendrocytes play a crucial role in our central nervous system (CNS) by myelinating axons for faster action potential conduction, protecting axons from degeneration, structuring the position of ion channels, and providing nutrients to neurons. Oligodendrocyte dysfunction and/or dysmyelination can contribute to a range of neurodegenerative diseases and neuropsychiatric disorders such as Multiple Sclerosis (MS), Leukodystrophy (LD), Schizophrenia (SCZ), and Autism Spectrum Disorder (ASD). Common characteristics identified across these disorders were either an inability of oligodendrocytes to remyelinate after degeneration or defects in oligodendrocyte development and maturation. Unfortunately, the causal mechanisms of oligodendrocyte dysfunction are still uncertain, and therapeutic targets remain elusive. Many studies rely on the use of animal models to identify the molecular and cellular mechanisms behind these disorders, however, such studies face species-specific challenges and therefore lack translatability. The use of human induced pluripotent stem cells (hiPSCs) to model neurological diseases is becoming a powerful new tool, improving our understanding of pathophysiology and capacity to explore therapeutic targets. Here, we focus on the application of hiPSC-derived oligodendrocyte model systems to model disorders caused by oligodendrocyte dysregulation.

Human iPSC-derived myelinating organoids and globoid cells to study Krabbe Disease

“…Altogether, these studies show that Kd impacts neurodevelopment in iPSC-derived 2D cultures but none of them explored myelination, which is largely impacted in Kd. In line with this, we used a 3D culture method that produces robust myelination (James et al, 2021) among the several approaches to induce iPSC differentiation into oligodendrocyte and myelination (Shim et al, 2023) and were able to replicate, for the first time, the demyelinating phenotype observed in Kd using iPSC-derived cultures.…”

Identity and Maturity of iPSC-Derived Oligodendrocytes in 2D and Organoid Systems

“…The generation of oligodendrocytes from stem cells in 2D models tremendously expanded our knowledge regarding different aspects of oligodendrocyte biology in health and disease, which includes epigenetic changes governing cellular development, heterogeneity, and functional genetics, among others [49][50][51]. For a more detailed and comprehensive survey of the differentiation of oligodendrocytes in 2D culture using additional approaches, we would refer readers to a few recently published reviews [52,53].…”