Single-cell RNA sequencing reveals functional heterogeneity of glioma-associated brain macrophages

Area of Science:

• Neuroscience
• Immunology
• Oncology

Background:

• Microglia, the brain's resident immune cells, play roles in CNS homeostasis and disease.
• Myeloid cells, including microglia and macrophages, infiltrate and support glioblastoma growth, with higher prevalence in males.
• The heterogeneity and function of myeloid cell subpopulations in gliomas are not well understood.

Purpose of the Study:

• To investigate the molecular heterogeneity and functional phenotypes of myeloid cell subpopulations in the brain during glioma development.
• To identify distinct profiles of microglia, infiltrating monocytes/macrophages, and CNS border-associated macrophages in glioma models.
• To explore potential sex-specific differences in myeloid cell responses to gliomas.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of CD11b+ myeloid cells from naïve and GL261 glioma-bearing mouse brains.
• Validation of identified marker proteins and analysis of spatial distribution of myeloid subsets.
• Analysis of bulk and scRNA-seq data from human diffuse gliomas.

Main Results:

• Identification of distinct molecular profiles for microglia, infiltrating monocytes/macrophages, and CNS border-associated macrophages in both naïve and glioma-bearing brains.
• Demonstration of significant molecular heterogeneity among myeloid cells.
• Discovery of higher expression of MHCII encoding genes in glioma-activated male microglia, consistent with human glioma data.

Conclusions:

• Glioma development is associated with unforeseen molecular heterogeneity within CNS myeloid cell populations.
• Sex-specific gene expression in glioma-activated microglia, particularly elevated MHCII in males, may contribute to glioma incidence and patient outcomes.
• These findings highlight the importance of considering sex as a biological variable in glioma research and treatment.