These stem cells show gene expression patterns that regulate early brain development and, when disrupted, could lead to neurological conditions.
Key Facts Stem Cell Discovery: A stem cell capable of maturing into three brain cell types may drive glioblastoma growth.
They made the discovery while taking a broad genomic survey of human brain cells from the first two decades of life.
As the researchers sifted through their data, Wang noticed a group of stem cells that seemed poised to do something unusual.
But these stem cells could mature into three lineages: two types of support cells known as glia, and one type of neuron.
In summary, scientists have discovered a special stem cell in the developing brain that can differentiate into several different cell types, which may help to explain the causes of glioblastoma and autism. When disturbed, these stem cells’ gene expression patterns that control early brain development may result in neurological disorders.
The study offers a thorough gene expression map that connects genes linked to autism to developing neurons that are active during brain development. The results pave the way to better understand the developmental foundations of autism and target the causes of glioblastoma.
Key Facts.
Glioblastoma growth may be fueled by a stem cell that can differentiate into three different types of brain cells.
Autism Insight: Genes linked to autism are active during critical phases of brain development, which may have an impact on the growth of neurons.
Innovative Mapping: Connections between development and illness are revealed by a thorough map of brain cell gene expression.
UCSF is the source.
The young brain contains a stem cell that can develop into the cells found in tumors, according to research from UCSF. The discovery may help to explain how adult brain cells exploit developmental processes to cause the rapid growth observed in brain cancers that are fatal, such as glioblastoma.
The discovery was made during a comprehensive genomic survey of human brain cells from the first 20 years of life. The results are visible in Jan. Eight in the natural world.
Arnold Kriegstein, MD, PhD, a professor of neurology at UCSF and co-corresponding author of the study, stated, “A lot of brain diseases start at different stages of development, but up until now we haven’t had a comprehensive roadmap for simply understanding healthy brain development.”.
“The genetic programs that underlie the development of the human brain and malfunction in certain types of brain dysfunction are highlighted in our map. “.”.
Gene expression in cells extracted from donated brain samples was measured for the study. In order to better understand how the brain forms connections, the researchers recorded each cell’s initial location.
The data included clues about the genesis of autism as well as the identification of an early stem cell that may help explain the genetics of glioblastoma in adulthood. To help the field better understand a variety of other brain disorders, the researchers have published the data.
As co-first and co-corresponding author of the paper, Li Wang, PhD, a postdoctoral researcher in Kriegstein’s lab, said, “Our study paints one of the most detailed pictures of human brain development.”.
We’re eager to see what else the field can do with this hard data, which can now be used to test theories based on observations made in the lab and clinic. “.”.
A wealth is revealed by the samples.
Animal models are used for the majority of research on the developing brain, and they are only loose representations of the human brain.
Co-first author Cheng Wang, PhD, and co-corresponding author Jingjing Li, PhD, led the team, which also bet that studying the human brain itself could yield important new insights. To collect brain samples, they collaborated with nearby hospitals connected to UCSF and the NeuroBioBank at the National Institutes of Health.
These samples, which came from 27 people ranging in age from infancy to adolescence, were sent to UCSF to be examined for gene expression in thousands of individual cells.
The process by which DNA, which is stored in chromosomes, is converted into RNA—short-lived genetic messages—and used as a template to create proteins is known as gene expression. Through RNA measurement, the researchers were able to observe how those cells behaved.
Kriegstein stated, “RNA degrades quickly, and you need to have very pristine tissue in order to get usable data.”.
Li and his colleagues’ ability to conduct such high-resolution genomic tests on this tissue was a significant advancement, and we are grateful to the community for contributing this priceless tissue to support such important research. “.”.
The researchers examined the regions of each chromosome that each cell could use for gene expression. Additionally, they identified the location in the brain from which each cell was extracted.
In order to better understand how humans learn, remember, and speak, the researchers concentrated on cells extracted from the front and rear of the cerebral cortex.
Wang claimed that RNA by itself is unable to fully describe a cell’s behavior.
We may be able to unravel the complete story of brain development if we measure the chromatin and RNA states simultaneously in the same cell and then map each cell back into the structure of the brain. “”.
In the developing brain, a variety of genes linked to autism risk appear.
Numerous gene mutations work together to cause autism rather than a single gene mutation.
The researchers discovered that immature neurons activated many of the genes associated with autism long before any symptoms would have appeared. They claimed that mutations in these genes might disrupt the developing young brain and cause autism.
“When young neurons were still moving throughout the developing brain and learning how to connect with other neurons, these gene expression programs became active,” Wang explained.
“Those developing neurons may become confused about where to go or what to do if something goes wrong at this point. “”.
The precise way autism develops in the brain is still unknown because the study did not examine tissue from people who have the disorder. However, the evidence connects the cells that form the foundation of the developing brain to numerous genetic variations linked to autism.
“We’ve identified many of the .s driving autism during a critical point in development,” Kriegstein said, adding that people often discuss “connecting the .s to come up with a picture of how autism emerges.”.
In order to unravel all the enigmas surrounding autism, this area of development may merit additional research. “”.
Could a program designed to promote brain growth in childhood be hijacked to promote tumor growth in later life?
A cluster of stem cells that appeared ready to do something out of the ordinary caught Wang’s attention as the researchers sorted through their data. Genes typically present in three mature cell types were now being expressed by these immature cells.
The developing brain contains a large number of stem cells that develop into a single cell type, such as a support cell or neuron. A few may develop into two varieties. However, these stem cells have the potential to develop into three lineages: one type of neuron, two types of glia, which are support cells.
This capability, according to the researchers, may allow it to develop into glioblastoma tumors later in life, which are composed of three related cell types.
Kriegstein remarked, “Glioblastoma has been difficult because it’s so diverse.”. “Li discovered a precursor that could produce all three types of glioblastoma cells.”. “”.
The finding supports the widely accepted hypothesis that tumors use genetic growth programs to cause uncontrollably high adult growth.
Additionally, it might offer a fresh approach to treating glioblastoma at its root cause: “cancer stem cell.”. “.”.
When it recurs during cancer, Wang said, “we may be able to stop that growth by knowing the context in which one stem cell produces three cell types in the developing brain.”.
UCSF authors Juan A., Li, Kriegstein, Wang, and Wang are also listed. Arantxa Cebrián-Silla, PhD; Moriano, PhD; Songcang Chen, MD; Guolong Zuo, PhD; Shaobo Zhang, MD; Tanzila Mukhtar, PhD; Shaohui Wang; Mengyi Song, PhD; Lilian Gomes de Oliveira, MA; Qiuli Bi, Jonathan J. Augustin, PhD; Mercedes F.; Xinxin Ge, PhD. PhD, Eric J. Paredes, M.D. Xin Duan, PhD; Huang, MD, PhD; and Arturo Alvarez-Buylla, PhD.
Disclosures and funding: NIH grants (U01MH114825, R35NS097305, P01NS083513, R01NS123912, K99MH131832) partially funded this work. At Neurona Therapeutics, Kriegstein serves as a director, consultant, and co-founder. Refer to the paper for all other funding.
About this research news on autism, brain cancer, and genetics.
Levi Gadye wrote this.
The UCSF is the source.
Levi Gadye at UCSF can be reached.
Image: Neuroscience News is credited with this image.
Open access to original research.
Human neocortex development: molecular and cellular dynamics by Arnold Kriegstein et al. nature.
abstract.
cellular and molecular dynamics of the human neocortex during development.
Gene regulation governs intricate cellular trajectories in the highly dynamic development of the human neocortex.
Using 38 human neocortical samples that included the prefrontal cortex and the primary visual cortex, we gathered paired single-nucleus chromatin accessibility and transcriptome data.
From the first trimester to adolescence, these samples cover the five major developmental phases.
In order to demonstrate spatial organization and intercellular communication, we concurrently conducted spatial transcriptomic analysis on a subset of the samples.
We can catalog gene regulatory networks underlying neural differentiation that are specific to cell types, ages, and geographical locations thanks to this atlas.
We have also broken down the intricate lineage relationships between progenitor subtypes during the neurogenesis-to-gliogenesis transition by combining lineage-tracing, progenitor purification, and single-cell profiling experiments.
GABAergic neurons, oligodendrocyte precursor cells, and astrocytes are produced locally by a subtype of tripotential intermediate progenitor cells known as tripotential intermediate progenitor cells (Tri-IPCs).
Notably, the majority of glioblastoma cells share transcriptome similarities with Tri-IPCs, indicating that cancer cells alter developmental processes to promote heterogeneity and growth.
Furthermore, we developed a disease-risk map that highlights enriched risk linked to autism spectrum disorder in second-trimester intratelencephalic neurons by combining our atlas data with extensive genome-wide association study data.
The cellular and molecular dynamics of the growing human neocortex are clarified by our research.
