Ependymal cells undergo astrocyte‐like reactivity in response to neuroinflammation

Abstract Ependymal cells form a specialized brain–cerebrospinal fluid (CSF) interface and regulate local CSF microcirculation. It is becoming increasingly recognized that ependymal cells assume a reactive state in response to aging and disease, including conditions involving hypoxia, hydrocephalus, neurodegeneration, and neuroinflammation. Yet what transcriptional signatures govern these reactive states and whether this reactivity shares any similarities with classical descriptions of glial reactivity (i.e., in astrocytes) remain largely unexplored. Using single‐cell transcriptomics, we interrogated this phenomenon by directly comparing the reactive ependymal cell transcriptome to the reactive astrocyte transcriptome using a well‐established model of autoimmune‐mediated neuroinflammation (MOG 35‐55 EAE). In doing so, we unveiled core glial reactivity‐associated genes that defined the reactive ependymal cell and astrocyte response to MOG 35‐55 EAE. Interestingly, known reactive astrocyte genes from other CNS injury/disease contexts were also up‐regulated by MOG 35‐55 EAE ependymal cells, suggesting that this state may be conserved in response to a variety of pathologies. We were also able to recapitulate features of the reactive ependymal cell state acutely using a classic neuroinflammatory cocktail (IFNγ/LPS) both in vitro and in vivo. Taken together, by comparing reactive ependymal cells and astrocytes, we identified a conserved signature underlying glial reactivity that was present in several neuroinflammatory contexts. Future work will explore the mechanisms driving ependymal reactivity and assess downstream functional consequences. image