Abstract

Central nervous system (CNS) lesions become surrounded by neuroprotective borders of newly proliferated reactive astrocytes. Fundamental features of these cells are poorly understood. Here, we show that 90% of border-forming astrocytes derive from proliferating Aldh1l1-expressing local astrocytes, and 10% from Pdgfra-expressing oligodendrocyte progenitors in mice. Temporal transcriptome analysis, snRNAseq and immunohistochemistry showed that after CNS injury, local mature astrocytes dedifferentiated, proliferated, and became transcriptionally reprogrammed to permanently altered new functional states, with persisting downregulation of molecules associated with astrocyte-neuron interactions, and upregulation of molecules associated with wound healing, microbial defense, and interactions with stromal and immune cells. Our findings show that at CNS injury sites, local mature astrocytes proliferate and adopt canonical features of essential wound repair cells that persist in adaptive states and are the predominant source of neuroprotective borders that re-establish CNS integrity by separating neural parenchyma from stromal and immune cells as occurs throughout the healthy CNS.