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Stanford Team Uses Single-Cell RNA-Seq to Characterize Human Brain Cells

NEW YORK (GenomeWeb) – In a study appearing online this week in the Proceedings of the National Academy of Sciences, Stanford University researcher Stephen Quake and colleagues presented results from a single-cell transcriptome sequencing study of human brain cells.

The team did single-cell RNA sequencing on almost 500 adult or fetal brain cells, plucked from cortical brain regions. The resulting transcriptional sequences broadly clustered the cells of all of the brain's main sub-types — from microglia and astrocytes to neurons. But they also revealed clusters that coincided with neuronal sub-populations that varied by location and developmental stage.

"These results lay the groundwork for the construction of a cellular map of the human brain that can be completed through the analysis of a larger number of cells from different anatomical regions of the brain," Quake and co-authors wrote.

"Such a map will help us identify specific markers for neuronal, glial, and vascular subtypes that we can link with information on location, connectivity, and electrophysiological properties in an attempt to fully elucidate the cellular complexity of the human brain," they added.

For the most part, studies of the human brain have hinged on either fine-scale profiling of bulk populations of post-mortem cells or in situ techniques that allow a look at a small set of genes or proteins in cells that have roughly retained their original context in the brain.

For the current study, the team took advantage of healthy neurons obtained from living individuals during surgical treatment for seizures — a procedure that involves removing miniscule bits of the cerebral cortex's anterior temporal lobe to reach sclerotic or otherwise injured brain tissue below.

Along with samples from eight adults undergoing such surgeries, the researchers also looked at cells from four fetal brain samples taken at between 16 and 18 weeks gestation, successfully generating single-cell RNA sequence profiles on 466 individual cortical cells in all.

Full transcriptional signatures in the cells defined 10 broad cell types, ranging from microglia, astrocytes, oligodendrocytes, and neurons to precursor cells and cells that didn't clearly fit into any already-defined cell types. When the team grouped cells by focusing on the most cell type-specific genes expressed, meanwhile, it saw slightly fewer clusters.

At a finer scale, the researchers found that the 113 adult neuronal cells profiled fell into seven sub-categories, including five groups of inhibitory neurons and two clusters of excitatory neurons.

Finally, the single-cell transcripts allowed the team to start teasing apart gene expression features that differ in mouse and human brain cells as well as transcriptional patterns that distinguish adult neurons from new and burgeoning neuronal cells in the fetal brain.

For instance, transcriptional patterns in individual neurons suggest that neuronal cells in the fetal brain are quite distinct from those found in the adult brain, revealing some features found in still-replicating brain cells. 

On the other hand, a subset of the adult neurons expressed immune-related genes from major histocompatibility complex class I, arguing against the notion that neurons are immune privileged and lacking in immunological activity.