Single-cell Transcriptomics Analyses Revealed Specialized Microglial Subsets with Oligodendrocyte-like Signatures

Background

Microglial heterogeneity is a fundamental feature of brain homeostasis and pathology. The purpose of this study was to investigate the complexity of microglial plasticity by characterizing specialized oligodendrocyte-like microglial subsets.

Methods

The study was performed utilizing single-cell transcriptomics analyses and immunofluorescence staining to identify and profile microglial subpopulations. Additionally, spatial transferring and morphological analyses were conducted to determine the anatomical distribution and structural features of these specific cells.

Results

We identified a distinct microglial subset termed dual-phenotype microglia (DPM), which co-expresses microglial and oligodendrocyte markers. DPM consisted of two subtypes with distinct functions: myelin-associated DPM (mDPM) and neuron-associated DPM (nDPM). Spatial and morphological evaluations revealed that mDPMs were sparsely distributed across the whole brain and exhibited a highly ramified architecture, whereas nDPMs were enriched in the hippocampal dentate gyrus. Mechanistically, we found that mDPM function was driven by the Sox10 regulon to modulate myelin maintenance and axonal ensheathment, while nDPM was orchestrated by Glis2, facilitating essential neuron-glia crosstalk and synaptic regulation. Furthermore, we demonstrated that nDPM and mDPM were predicted to undergo significant alterations in multiple sclerosis and Alzheimer’s disease. Notably, mDPMs were selectively enriched in active multiple sclerosis lesions, revealing that DPM were closely related to neuropsychiatric disorders.

Conclusions

By comprehensively characterizing the morphology, molecular signatures, and spatial logic of these oligodendrocyte-like microglial subsets, our study elucidated the complexity of microglial plasticity. These findings provided new insights into their diverse roles in central nervous system health and disease.

Identification, Molecular Profiling, and Functional Modeling of Dual-Phenotype Microglia (DPM). ( 1 ) Discovery: Identification of the dual-phenotype microglia (DPM) population through single-cell transcriptomics. ( 2 ) Molecular Signatures: The transcriptomic identity of DPM subtypes is governed by specific regulatory networks. ( 3 ) Distribution & Pathology: Spatial mapping reveals divergent anatomical logic and disease relations for DPM subtypes. ( 4 ) Mechanism/Theory: A proposed functional model of mDPMs as “metabolic relay” and support units.