Insights into neurodevelopmental features of Huntington's disease from stem cell-derived models including organoids

Two- and three-dimensional (2D and 3D) cell models derived from human stem cells have shed light on a wide range of molecular and cellular features of Huntington's disease (HD). Here we review the use of human stem cell-derived models to explore neurodevelopmental contributions to HD. We provide a timeline of key advances made in 2D and 3D model systems, ranging from differentiated monocultures to brain-like organoids and assembloids. Models along this spectrum have advanced our understanding of various disease-associated characteristics including disease protein (huntingtin) aggregation, somatic repeat instability, transcriptional dysregulation, perturbations in neurodevelopmental staging, and neural circuitry. We highlight recent findings in brain-like organoids which, despite being a relatively recent innovation, are proving to be a promising tool with which to study aberrant neurodevelopmental features of HD. All models have their limitations, and we compare and contrast the utility and limitations of various stem cell-based methods to study HD. Finally, we speculate on future advances employing advanced computational and transcriptomic methods that will expand the power of 3D model systems for the study of HD and related neurodegenerative disorders.