Transcriptomic atlas and interaction networks of brain cells in mouse CNS demyelination and remyelination

SUMMARY

Demyelination is a hallmark of multiple sclerosis, leukoencephalopathies, cerebral vasculopathies, and several neurodegenerative diseases. The cuprizone mouse model is widely used to simulate demyelination and remyelination occurring in these diseases. Here, we present a high-resolution single-nucleus RNA sequencing (snRNA-seq) analysis of gene expression changes across all brain cells in this model. We define demyelination-associated oligodendrocytes (DOLs) and remyelination-associated MAFB ^hi microglia, as well as astrocytes and vascular cells with signatures of altered metabolism, oxidative stress, and interferon response. Furthermore, snRNA-seq provides insights into how brain cell types connect and interact, defining complex circuitries that impact demyelination and remyelination. As an explicative example, perturbation of microglia caused by TREM2 deficiency indirectly impairs the induction of DOLs. Altogether, this study provides a rich resource for future studies investigating mechanisms underlying demyelinating diseases.

In brief

Hou et al. identify key transcriptional signatures of brain glial and vascular cells during demyelination and remyelination induced by cuprizone using single-nucleus RNA sequencing. They reveal cell-cell interactions that impact these processes and demonstrate that a population of demyelination-associated oligodendrocytes is dependent on a TREM2-mediated microglia response.

Graphical Abstract