Measurable dissimilarities in the patterns and speed of development in autism spectrum disorder-derived cells have been uncovered by researchers at the Salk Institute. They compared stem cells created from individuals with autism spectrum disorder (ASD) against stem cells created from those without ASD.
The results could lead to diagnostic methods to detect ASD at an early stage, when preventive interventions could potentially take place.
“Although our work only examined cells in cultures, it may help us understand how early changes in gene expression could lead to altered brain development in individuals with ASD. We hope that this work will open up new ways to study neuropsychiatric and neurodevelopmental disorders."
said senior author Professor Rusty Gage, president of the Salk Institute.
Neural Stem Cells
The researchers took skin cells from eight people with ASD and five people without ASD and turned them into pluripotent stem cells — cells that have the ability to develop into any cell type. They then coaxed the stem cells to develop along the path of becoming neurons by exposing them to certain chemical factors.
Through the use of molecular “snapshots” from different developmental stages in the stem cells, the team was able to track genetic programs that switched on in a certain order as the stem cells developed into neurons. This revealed key differences in the cells derived from people with ASD.
For example, the Salk team observed that the genetic program associated with the neural stem-cell stage turned on earlier in the ASD cells than it did in the cells from those without ASD. This genetic program includes many genes that have been associated with higher chances of ASD.
In addition, the neurons that eventually developed from the people with ASD grew faster and had more complex branches than those from the control group.
The researchers say the experiments in this study will lead to more dynamic approaches for studying the mechanisms that are involved in ASD predisposition and progression.
“It’s currently hypothesized that abnormalities in early brain development lead to autism, but the transition from a normally developing brain to an ASD diagnosis is blurred. A major challenge in the field has been to determine the critical developmental periods and their associated cellular states. This research could provide a basis for discovering the common pathological traits that emerge during ASD development,"
said first author Simon Schafer, a postdoctoral fellow in the Gage lab.
The team plans to focus next on the creation of brain organoids, three-dimensional models of brain development in a dish that enable scientists to study the interactions between different types of brain cells.
Autism spectrum disorder is a relatively common developmental disorder of communication and behavior that affects about 1 in 59 children in the US, according to the Centers for Disease Control and Prevention. Despite its prevalence, it is still unclear what causes the disease and what are the best ways to treat it.
Simon T. Schafer, Apua C. M. Paquola, Shani Stern, David Gosselin, Manching Ku, Monique Pena, Thomas J. M. Kuret, Marvin Liyanage, Abed AlFatah Mansour, Baptiste N. Jaeger, Maria C. Marchetto, Christopher K. Glass, Jerome Mertens & Fred H. Gage Pathological priming causes developmental gene network heterochronicity in autistic subject-derived neurons Nature Neuroscience (2019) doi: https://doi.org/10.1038/s41593-018-0295-x
Image: a two-dimensional culture of subject-derived cortical neurons stained for neuronal markers MAP2 (red) and Tuj1 (green). Credit: Salk Institute