Researchers have discovered of a new type of stem cell in the brain that could lead to the development of more effective treatments in adult patients with glioblastoma, according to a recent study published by Wang et al in Nature. The finding could help explain how adult brain cells take advantage of developmental processes to instigate the growth seen in brain cancers like glioblastoma.
Background
Glioblastoma is one of the deadliest types of brain tumors.
Most studies of the developing brain are carried out in animal models, which are at best loose proxies for the human brain.
“Many brain diseases begin during different stages of development, but until now, we haven’t had a comprehensive roadmap for simply understanding healthy brain development,” explained senior study author Arnold Kriegstein, MD, PhD, Professor of Neurology at the University of California, San Francisco (UCSF). “Our map highlights the genetic programs behind the growth of the human brain that go awry during specific forms of brain dysfunction,” he continued.
Study Methods and Results
In the study, the researchers conducted a broad genomic survey of human brain cells from the first two decades of life. They proposed that valuable new insights could be made by studying the human brain itself and worked with the National Institutes of Health’s (NIH) NeuroBioBank and local hospitals associated with UCSF to obtain brain samples. These samples, donated from 27 individuals from early life through adolescence, were sent to the researchers and analyzed for gene expression in thousands of individual cells. Gene expression refers to how DNA is copied into RNA, which is then used as a template for building proteins. By measuring RNA, the researchers could peer into the behavior of those cells. They kept track of the original location of each cell to help explain how the brain creates connections.
“RNA degrades quickly, and you need to have very pristine tissue in order to get usable data,” Dr. Kriegstein said. “It was a huge advance … to perform such high-resolution genomic tests on this tissue, and we thank the community for supporting such critical research by donating this precious tissue,” he added.
The researchers then analyzed which parts of each chromosome were available for expressing genes in each cell and labeled where each cell had been taken from in the brain—focusing on cells taken from the front and the back of the cerebral cortex, regions that in humans are responsible for learning, memory, and language.
“RNA alone doesn’t tell the entire story of a cell’s behavior. By measuring RNA and chromatin state at the same time in the same cell and then mapping each cell back into the brain’s structure, we could begin to understand the full story of brain development,” detailed lead study author Li Wang, PhD, a postdoctoral researcher in Dr. Kriegstein’s laboratory at UCSF.
The researchers revealed that a stem cell in the young brain is capable of forming the cells found in tumors. They identified a group of stem cells that had begun to express genes normally found across three mature cell types. Many stem cells in the developing brain mature into just one cell type such as a neuron or a support cell. Some can mature into two types, but these stem cells could mature into three lineages: two types of support cells known as glia, and one type of neuron. The researchers thought this ability might enable it to give rise later in life to glioblastoma, which contain three similar cell types.
Further Findings
In addition to the discovery of an early stem cell that could explain the genetics of glioblastoma in adulthood, the data contained indications about the origins of autism.
Autism isn’t caused by a single gene mutation, but rather by the combination of many gene mutations. The researchers found that many of the genes that correlate with autism were turned on by immature neurons prior to the emergence of any symptoms. Mutations in these genes could interfere with the growth of the young brain, leading to autism.
“These programs of gene expression became active when young neurons were still migrating throughout the growing brain and figuring out how to build connections with other neurons. If something goes wrong at this stage, those maturing neurons might become confused about where to go or what to do,” stated Dr. Wang.
Since the study didn’t examine tissue from patients with autism, the researchers noted that it’s still unclear how autism develops in the brain; however, the data link many genetic variations associated with autism to the cells that serve as the building blocks for the growing brain.
“[Researchers] talk about connecting the dots to come up with a picture of how autism emerges, and in a sense, we've identified many of the dots driving autism during a critical point in development. This part of development could be worthy of further investigation for untangling all the mysteries of autism,” Dr. Kriegstein indicated.
Conclusions
“Glioblastoma has been challenging because it's so heterogeneous. [We] found a precursor capable of making all three glioblastoma cell types,” Dr. Kriegstein underlined.
The findings validated a widely held theory that tumors may hijack genetic growth programs for out-of-control growth in adulthood. The research may provide new opportunities for treating glioblastoma at its source: the cancer stem cell.
“Our study paints one of the most detailed pictures of human brain development,” highlighted Dr. Wang. “Theories based on observations in the clinic and laboratory can now be tested against this hard data, and we’re excited to see what else the field can do with it,” he emphasized.
The researchers have published their data as a resource for the field to use for understanding a wide range of other brain disorders.
“By understanding the context in which one stem cell produces three cell types in the developing brain, we could be able to interrupt that growth when it reappears during cancer,” Dr. Wang concluded.
Disclosure: The research in this study was supported in part by grants from the NIH. For full disclosures of the study authors, visit nature.com.
