Preprint The Human Microglia Atlas HuMicA Unravels Changes in Homeostatic and Disease-Associated Microglia Subsets across Neurodegenerative Conditions, 2023

SNT Gatchaman

SNT Gatchaman

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The Human Microglia Atlas HuMicA Unravels Changes in Homeostatic and Disease-Associated Microglia Subsets across Neurodegenerative Conditions
Ricardo Martins-Ferreira; Josep Calafell-Segura; Barbara Leal; Javier Rodriguez-Ubreva; Elisabetta Mereu; Paulo Pinho e Costa; Esteban Ballestar

Dysregulated microglia activation, leading to neuroinflammation, is currently considered to be of major relevance in the development and progression of neurodegenerative diseases. The initial M1/M2 dual activation classification for microglia is now considered outdated. Even the "disease-associated microglia" (DAM) phenotype, firstly described in mice, has proven insufficient to precisely represent the multitude of microglia phenotypes in pathology.

In this study, we have constructed a transcriptomic atlas of human brain immune cells by integrating single-nucleus (sn)RNA-seq datasets from multiple neurodegenerative conditions. Sixteen datasets were included, comprising 295 samples from patients with Alzheimer's disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) dataset included 60,557 nuclei and revealed 11 microglial subpopulations distributed across all pathological and healthy conditions. Among these, we identified four different homeostatic clusters as well as pathological phenotypes. These included two stages of early and late activation of the DAM phenotype and the disease-inflammatory macrophage (DIM) phenotype, which was recently described in mice, and is also present in human microglia, as indicated by our analysis. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution to the establishment of pathological phenotypes.

Our analysis showed overall depletion of four substates of homeostatic microglia, and expansion of niche subpopulations within the DAM and DIM spectrum across distinct neurodegenerative pathologies. The HuMicA is an invaluable resource tool used to support further advances in the study of microglia biology through healthy and disease settings.

Link | PDF (Preprint: BioRxiv)
 
It can be inferred that the plasticity of microglial function in homeostasis and injury/disease may follow a multi-subpopulation pattern influenced by the type of disease, sex, age and even spatial localization17,18.
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Of the 64,438 immune cell nuclei from brain samples from people with various diseases and healthy people, almost all 60,557 nuclei were from microglia. The cell sorting identified 15 clusters, 11 of which were microglia.

The clustering analysis of the 64,438 immune cell nuclei resulted in the identification of 15 clusters (Figure 1B), annotated 0 to 14 in descending order based on the total number of nuclei per cluster (Figure 1C). These clusters were distributed across all neurological and healthy settings (Supplementary Figure 4 and Supplementary Table 2). As expected, microglia were naturally the predominant cell type. In addition, we annotated clusters corresponding to other immune cell populations, including macrophages and T cells.
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There's a reference to doublet cells, which is when two cells are treated as one in the sorting, incorrectly creating new classes of cells with the markers of both cells. So they are regarded as mistakes of the flow cytometry process and, in this case, two such classes were discarded. The researchers calculated the mean number of genes per apparent nuclei, so that indicates when there is the doublet problem.

There's some speculation about some classes of microglia that also present markers of other cell types. For example, Cluster 6 showed markers of oligodendrocytes. Cluster 6 was found to be expanded in multiple sclerosis, it seems to be associated with myelin phagocytosis.

This creation of the atlas is wonderful - a baseline for subsequent findings to be compared against. It feels like there are quite a lot of new tools and they are generating all sorts of possibilities for research.
 
We observed that homeostatic microglia from neurodegenerative patients displayed upregulation of genes associated with microglia activation and pro-inflammation.
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I think this sort of analysis could tell us quite a bit about what is going on in LC and ME/CFS brains. But we'd need access to brains. We'd need brain banks.
 
Hutan said:
I think this sort of analysis could tell us quite a bit about what is going on in LC and ME/CFS brains. But we'd need access to brains. We'd need brain banks.
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I think we got that. Did we get that? I'm pretty sure at least Polybio has that.

But yeah we need more brains. Which sounds both creepy and interesting.
 
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