Traumatic brain injuries (TBIs) happen when a person is subjected to a blow or jolt to the head, or when a penetrating injury like a gunshot occurs. These injuries affect how the brain works, and are a leading cause of disability and death in young people in the US. They also affect older individuals who are more prone to falling. There can be serious long-term effects from TBIs, such as difficulties with cognition, or communication; emotional and behavioral disorders; and sensory issues such as ringing in the ears or double vision. TBI may also increase the risk of neurodegenerative diseases, and they can shorten life expectancy by as much as nine years.
Scientists have now used human cerebral organoids, which are miniature, simplified models of the human brain, to demonstrate that mild and moderate TBI can have a major impact on gene expression in the brain. This model could present a far more accurate picture of what happens in the human brain after TBI compared to animal models.
"This is a new approach to deepening our understanding of traumatic brain injury using engineered human-specific models," said Pascal Zinn, a neurosurgical oncologist at UPMC Hillman Cancer Center. "We hope this research will save lives."
In this work, the researchers had to create the cerebral organoids, which are made with induced pluripotent stem cells that have been programmed to express the genes that will lead to the creation of brain cells. The cells were also physically spun so they would take on a spherical shape. Then, the organoids were 'loaded' to mimic brain injury, and the severity of the injury was measured by assessing calcium ion levels; as calcium ion levels increase, injuries are more severe. Finally, the investigators assessed gene expression in the organoid cells by sequencing the RNA, which reveals the active genes. The findings have been published in Scientific Reports.
"This is the first time researchers have explored RNA sequencing to understand what happens both immediately after someone experiences a blow to the head and possible consequences in the long term," explained first study author Susana Beltrán. This work showed that the activity of genes that are related to cell death, cancer cell growth, and the regulation of white blood cells increased after an injury.
This work may help researchers and clinicians develop treatments for TBIs.
"We can imagine athletes susceptible to concussions adding a supplement to their regimen that can target those genes at risk of upregulation after TBI to either prevent or slow disease progression," said Beltrán. "Even beyond brain injury, we want to set the standard that human organoids can be used to model human disease."
Sources: Carnegie Mellon University Mechanical Engineering, Scientific Reports