Human Brain Cells: Single Cells as Sources for Brain Functioning?

24/10/2023

Article by: Emil Koch, on 24 October 2023, at 12:39 CEST

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The body contains around 50 - 100 trillion cells and 200 cell types. The brain comes no short in its collection, as put forward by 21 papers published in Science Advances and Science Translational Medicine. Can single-cell genomics make the difference?

National Institutes of Health's Brain Initiative Cell Census Network (BICCN) scientists conducted a comprehensive analysis of 75 tissue samples taken from patients undergoing brain surgery for epilepsy and tumors, as well as samples from 17 deceased children. Their research identified and characterized more than 3,000 distinct cell types within the human brain. Kim et al. (2023) analyzed scRNA-seq datasets derived from first-trimester samples of human development and identified the two subgroups of neurons, the OLIG3-positive thalamic radial glia, and IPCs. These are classified as progenitor cells. Additionally, they detected neural progenitors expressing ID3/ASCL1 with presumed GABAergic neuron offspring. Overall, the first trimester of diencephalic cell types is well-conserved in humans, according to Kim et al. (2023), which also indicates later GABAergic migratory streams than originally assumed. NEUROD1/LHX1+ IPCs (IPC) were enriched for MEIS1 and PAX3 in trimester two, suggesting the formation of the pretectum. The authors document the initial occurrence of gliogenesis in the human thalamus at approximately GW16. Lee el. al. (2023) further characterized the electrophysiological, morphological, and transcriptomic profiles of a diversity of GABAergic neuron subtypes by Patch-seq (patch-clamp electrophysiology plus single-cell RNA sequencing) experiments in human neocortical brain slices. They uncovered species differences in morphological and electrophysiological features of neocortical parvalbumin and somatostatin-expressing neuron homologous types, guiding future functional studies of human brain cell types on gene-function relationships.

A different team conducted scRNA-seq on posterior sections of the cerebellar vermis or paravermis obtained from 16 postmortem human donors aged between one and five years at the time of death. Ament et al. (2023) noted that the Mic1 and Mic3 immune cell subgroups were less abundant in cerebellar tissue from donors with inflammation. In other words, brain inflammation could potentially be linked to a change in microglial subgroups that display markers indicating a state of heightened pro-inflammatory activity. Considering that inflammation in early life is a well-established risk factor for various neurodevelopmental disorders, it is worth noting that Purkinje cells were confirmed in lower proportions in the brains of donors with inflammation, going in line with the reduced number and density of Purkinje cells in autism. In addition, elevated expression levels of autism risk genes, such as EBF3 and FOXP1, alongside genes involved in molecular adaptations associated with changes in adulthood, were elevated. This allows for the intriguing thought of whether autism partially results from inflammatory events in early childhood and genes and environment predisposing for that. Results from Chen et al. (2022) corroborate this idea, revealing associations between genetic variants for 15 different inflammatory regulators and possible links to neurodevelopmental disorders, including autism.

Interestingly, researchers discovered highly consistent patterns of cells among different individuals but saw some interindividual differences in microglia in the brain and their expressed genes. Similarly, only a few hundred genes mark the primary differences between human and primate brains, Jorstad et al. (2023) reported. These genes, primarily responsible for neural connections and the formation of brain circuits, are likely to hold the key to understanding the progressive increase in cognitive capabilities throughout human evolution - a matter of distinct wiring while retaining a fundamental brain cell architecture.

In summary, the human body is composed of a multitude of cells and a wide variety of cell types. The application of single-cell genomics holds the potential to enhance our comprehension of brain function and facilitate the creation of more precise brain maps. These advancements will not only illuminate our research into neurodevelopmental disorders but also shed light on the critical windows of early brain development and underlying cellular mechanisms.

References:

Chen, X., Yao, T., Cai, J., Fu, X., Hui-Ru, L., & Wu, J. (2022). Systemic inflammatory regulators and 7 major psychiatric disorders: A two-sample Mendelian randomization study. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 116, 110534. https://doi.org/10.1016/j.pnpbp.2022.110534.

Johansen, N., Somasundaram, S., Travaglini, K. J., Yanny, A. M., Shumyatcher, M., Casper, T., Cobbs, C., Dee, N., Ellenbogen, R. G., Ferreira, M., Goldy, J., Guzman, J., Gwinn, R. P., Hirschstein, D., Jorstad, N. L., Keene, C. D., Ko, A. L., Levi, B. P., Ojemann, J. G., . . . Miller, J. A. (2023). Interindividual variation in human cortical cell type abundance and expression. Science, 382(6667). https://doi.org/10.1126/science.adf2359.

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