SEGAs Are a Serious Concern for TSC Patients
Many people with tuberous sclerosis complex (TSC) develop growths in the brain near fluid-filled spaces called ventricles. Small ones showing no signs of growth are called subependymal nodules (SENs), but others grow over time and are called subependymal giant cell astrocytomas, or SEGAs. SEGAs are considered noncancerous, but they can cause serious problems — including blocking the flow of fluid in the brain, raising pressure inside the skull, triggering seizures, and contributing to learning and behavioral challenges. Understanding exactly what kinds of cells make up a SEGA has been an important but unanswered question in TSC research.
Researchers Built the First Cell-by-Cell Map of SEGAs
Scientists at Clemson University used a technique called single nuclei RNA sequencing — a method that reads the genetic “instruction messages” inside individual cells — to create the first detailed map of the cell types inside human SEGAs. The team obtained SEGA tissue samples from the TSC Alliance Biosample Repository, hosted at the Van Andel Institute, using tissue from four individuals with TSC ranging in age from 6 to 18, and compared them to matched brain tissue from people without TSC. In total, they identified 15 distinct groups of cells within the SEGAs.
SEGAs Are Mostly Made of Nerve Cells, Not Glial Cells
One of the most significant findings was that the most common cell type inside SEGAs was not the type of cell that the name “astrocytoma” implies. Despite being named after a type of brain support cell (astrocytes), SEGAs were found to be predominantly composed of nerve cells — specifically a type known as GABAergic neurons, which normally help control and calm brain activity. At least 40% of SEGA cells belonged to this neuronal category. Notably, these neurons showed signs of altered activity and had gene expression patterns linked to abnormal growth and development.
The Tumor Environment Is Also Distinctly Altered
Beyond neurons, the study revealed other important changes inside SEGAs compared to normal brain tissue:
- Blood vessels were more abundant — the number of endothelial cells (which line blood vessels) more than doubled in SEGAs, suggesting increased blood supply and possibly a leakier blood-brain barrier.
- Immune cells around blood vessels increased by nearly 300% — a type of cell called perivascular macrophages was far more common in SEGAs than in normal tissue.
- Myelin was reduced — the protective coating around nerve fibers (called myelin) was scarce in SEGAs, consistent with fewer mature oligodendrocytes, the cells that make myelin.
This Research Opens New Treatment Directions for TSC Patients
Understanding what types of cells make up SEGAs has direct implications for how they might be treated. Because SEGAs are rich in neurons with altered activity, therapies that modulate neuronal signaling — including drugs that affect neurotransmitter receptors — may be worth exploring as a way to slow or prevent SEGA growth. The increased blood vessel formation also suggests that drugs already approved for other brain tumors to block vessel growth could potentially be repurposed for SEGAs. The researchers also confirmed their findings in a mouse model of TSC, where removing the Tsc2 gene from neural stem cells produced SEGA-like growths with the same kinds of abnormal neurons found in human tissue. All sequencing data from this study have been made publicly available for other researchers to build on.
Lead author: David M. Feliciano, PhD, Associate Professor, Biological Sciences, Clemson University
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