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The human cerebral cortex is made up of different types of cells that interact with each other to play an important role in shaping and maintaining brain function. Single-cell transcription provides support for the characterization of different cellular molecular features in the cerebral cortex, but the spatial relationships between cells and the way they interact remain unclear.
Based on this, the Team of Zhuang Xiaowei of Harvard University published a research paper in Science Magazine titled "Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH."
Using multiple anti-error correction fluorescence in situ hybridization (MERFISH) technology, spatially resolved 4000 genes at the single-cell level, more than 100 cell populations with transcriptional differences were identified, the upper cell profile of the human temporal tyrannosa was mapped through differences in molecular definition and spatial structure, and the intercellular mode of action in the cerebral cortex was further explored.
Human cortex single-cell transcriptional composition and cell type classification
To identify single-cell expression profiles that transcribe different cell populations, the researchers used MERFISH technology to image 4,000 genes in the middle gyrus temporal gyrus (MTG) and supertemporal gyrus (STG) in brain samples, and found that there were a total of 125 differentially transcribed cell populations in human MTG and STG, including 29 excitatory cell populations, 39 inhibitory cell populations, and 57 non-neuronal cell populations. Quantitative analysis showed that human MTG and STG consisted of 26% excitatory neurons, 11% inhibitory neurons, and 63% non-neuronal cells.
Next, the researchers compared the differences in cell composition between the human and mouse cortex and observed that the human E (excitatory neurons): I (inhibitory neurons) ratio was 1/3 of that of mice. Among excitatory neurons, the proportion of non-telencephalic (IT) neurons decreased from 29% in mice to 7% in humans, indirectly indicating that it is dominant in human IT neurons and that the proportion of intracortex cell-to-cell communication is higher.
For inhibitory neurons, the proportion of human VIP neurons (the main type of inhibitory neurons) increases relative to mice, while VIP regulates the inhibition of excitatory neurons. Thus, the increase in the proportion of VIPs suggests a potential mechanism for human-dependent sensory processing and learning of relevant neuronal dynamics.
Figure 1. MERFISH technology performs spatially resolved single-cell transcriptome analysis of the human cortex
Spatial distribution of human and mouse cortical cells
The researchers identified cell types in situ by MERFISH and plotted the spatial distribution of cortical cells. IT neurons throughout the human cortex were found to be distributed in a layered manner, while other excitatory neurons were mainly distributed in the deep layers. At the cluster level, inhibitory neurons also employ layered tissues, and many clusters of inhibitory neurons are mainly confined to the layer and its sub-parts. In the mouse cortex, similar spatial distributions of neurons were also observed.
Non-neuronal cells also exhibit layered tissue in the human cortex. Oligodendrocytes are predominantly enriched in deeper layers and white matter. Astrocytes, microglia, OPCs, endothelial cells and parietal cells show layered tissues, but they show a gradually evolving cell composition pattern throughout the depth of the cortex.
Figure 2. Lamellar tissue structure of human and mouse cortical cell types
Cell interactions in the human and mouse cortex
MERFISH images show frequent cell contact or proximity between cells, which the researchers used to predict that cells interact through contact or paracrine. In terms of glial-vascular interaction, the researchers observed significant differences between humans and mice. MERFISH images show that human cortex oligodendrocytes and microglia often accumulate in endothelial cells and parietal cells to form perivascular structures compared to mice, which are more closely related. Quantitative analysis also confirmed that human microglia and oligodendrocytes have more contact with somatic cells of vascular formation.
Species differences in cell interactions have also been observed between neurons and glial cells. The frequency of contact between neurons and oligodendrocytes increases significantly in humans. Although this phenomenon has also been observed in mice, it does not occur at any rate that exceeds the random frequency.
In addition, the researchers identified ligand-receptor pairs of microglia and IT neurons from MERFISH data, and through single-molecule FISH measurements, further verified that some ligands and receptors are genetically associated with neurodegenerative diseases.
Figure 3.Interaction between specific types of cells in the human and mouse cortex
Summary
The study systematically describes neighboring cell-to-cell interactions by cell type specifically through high spatial resolution MERFISH atlases and reveals differences in cell-to-cell interactions between humans and mice. A comparison of the cerebral cortex of humans and mice found that the cellular layered tissue was conserved and that somatic interactions differed between species.
In addition, the relative enrichment of ligand receptor pairs associated with neurodegenerative disease genetics in microglia-neurons suggests a potential molecular basis for microglia-neuron interactions and a potential link between these cell interactions and neurodegenerative diseases.
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Fang R, Xia C, Close JL,et al. Conservation and divergence of cortical cell organization in human and mouse revealed by MERFISH. Science. 2022 Jul;377(6601):56-62. doi: 10.1126/science.abm1741. Epub 2022 Jun 30. PMID: 35771910; PMCID: PMC9262715.
Compiled by Banana Milk (Brainnews Creative Team)
Reviewer: Goku (Brainnews Editorial Office)