Scar formation is the replacement of parenchymal cells by stromal cells and fibrotic extracellular matrix. Until as recently as 25 years ago, little was known about the major functional contributions of different neural and non-neural cell types in the formation of scar tissue and tissue fibrosis in the CNS. Concepts about CNS scar formation are evolving rapidly with the availability of different types of loss-of-function technologies that allow mechanistic probing of cellular and molecular functions in models of CNS disorders in vivo. Such loss-of-function studies are beginning to reveal that scar formation and tissue fibrosis in the CNS involves complex interactions amongst multiple types of CNS glia and non-neural stromal cells. For example, attenuating functions of the CNS resident glial cells, astrocytes or microglia, can disrupt the formation of limitans borders that form around stromal cell scars, which leads to increased spread of inflammation, increased loss of neural tissue, and increased fibrosis. Insights are being gained into specific neuropathological mechanisms whereby specific dysfunctions of different types of CNS glia could cause or contribute to disorder-related tissue pathology and dysfunction. CNS glia, as well as fibrosis-producing stromal cells, are emerging as potential major contributors to diverse CNS disorders either through loss- or gain-of-functions, and are thereby emerging as important potential targets for interventions. In this article, we will review and discuss the effects on CNS scar formation and tissue repair of loss-of-function studies targeted at different specific cell types in various disorder models in vivo.

Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder^1-4. These changes include differentially expressed genes (DEGs) whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.