Article
Stem Cell Deletion Improves TBI Recovery in Mice
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In deleting the gene encoding of SOX2 in models inflicted with TBI, functional and behavioral recovery improved.
Chun-Li Zhang, PhD
Deleting a particular stem cell transcription factor could possibly aid the recovery of patients with traumatic brain injury (TBI).
In a study conducted by University of Texas Southwestern molecular biologists, adult mice with TBI benefitted from targeted stem cell transcription factor deletion. Researchers found that reactive astrocyte signaling pathways dependent on SOX2 — a crucial component for stem cells, cell reprogramming, and brain development — are targets for brain recovery following TBI.
In conditionally deleting the gene encoding of SOX2 in mouse models inflicted with TBI, along with astrocyte reactivity dampening, researchers were able to promote functional and behavioral recovery.
The discovery comes in lieu of the preconceived indication that reactive astrocytes — a large subgroup of glial cells which support and insulate neurons in the brain and spinal cord — are necessary for brain injury recovery.
Chun-Li Zhang, PhD, Associate Professor of Molecular Biology and a WW Caruth, Jr. Scholar in Biomedical Research in the Hamon Center for Regenerative Science and Medicine at UT Southwestern, expressed surprise at the contrary discovery.
“Our finding runs counter to the belief that increasing the reactivity of astrocytes and other glial cells in the brain helps maintain tissue integrity following TBI,”Zhang said. “That’s why the accelerated recovery from injury after deletion of the transcription factor in reactive astrocytes was unexpected.”
The mice included in the study were modified to allow conditional SOX2 gene deletion during adulthood. Researchers deleted the gene in some of the mouse models, left it intact in others as a control, and compared the 2 groups’ responsive recovery to TBI.
TBI, an impact to the head that can affect brain function, mental status, consciousness, and memory loss, is most commonly associated with concussions in human patients. Researchers used a controlled cortical impact to give mice TBI with an electromagnetically driven device.
Between 1 and 8 weeks following TBI, the models were tested with an elevated plus maze, a tail suspension test, a Morris water maze, and the modified neurologic severity score.
The TBI-induced mouse population reported better scores on behavior tests associated with the brain’s prefrontal cortex — the region responsible for regulating complex thought, emotion, and behavior in humans.
The deleted-SOX2 gene population also reported no significant effects to learning and memory, associated with the hippocampus region of the brain.
“Our results reveal that SOX2 plays an important role in TBI-induced reactive astrocytes and behavioral deficits,” Zhang said. “We look forward to exploring how SOX2-dependent pathways could be targeted for recovery after TBI.”
Zhang and researchers called for a better understanding of molecular mechanisms, and the control of reactive astrocyte function, in order to articulate therapeutic methods for TBI. Though SOX2 is known for its critical role in embryonic stem cells, neural stem cells, brain development, and adult neurogenesis, its differentiated cell function is not certain.
Still, the researchers concluded that the test results were unanticipated.
“It is unexpected that astrocyte-specific deletion of Sox2 in mice results in a much-reduced lesion size and significantly improved behavioral recovery after TBI,” researchers wrote. “Emerging evidence shows that reactive astrocytes are critical for restricting inflammation and preserving tissue and function.”
The study, "Astrocyte-Specific Deletion of Sox2 Promotes Functional Recovery After Traumatic Brain Injury," was published online in Cerebral Cortex last week.
A press release regarding the study was made available.
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