Glial Scar Borders Are Formed by Newly Proliferated, Elongated Astrocytes That Interact to Corral Inflammatory and Fibrotic Cells via STAT3-Dependent Mechanisms after Spinal Cord Injury

TLDR

Astroglial scars form around damaged CNS tissue after trauma, stroke, infection, or autoimmune inflammation, serving wound repair yet hindering axonal regrowth. The study seeks to elucidate the cellular mechanisms, regulation, and functions of astroglial scar formation to inform safe interventions for CNS disorders. Wild‑type and transgenic mice were used to quantify and dissect astroglial proliferation, morphology, and chemistry relative to lesion distance during scar development. Reactive astrocytes near spinal cord injury display heterogeneous phenotypes; at 14 days post‑injury, newly proliferated, elongated astroglia form dense mesh‑like borders that, via STAT3‑dependent mechanisms, corral inflammatory and fibrotic cells, and STAT3 deletion disrupts this organization, increasing inflammatory spread and neuronal loss.

Abstract

Astroglial scars surround damaged tissue after trauma, stroke, infection, or autoimmune inflammation in the CNS. They are essential for wound repair, but also interfere with axonal regrowth. A better understanding of the cellular mechanisms, regulation, and functions of astroglial scar formation is fundamental to developing safe interventions for many CNS disorders. We used wild-type and transgenic mice to quantify and dissect these parameters. Adjacent to crush spinal cord injury (SCI), reactive astrocytes exhibited heterogeneous phenotypes as regards proliferation, morphology, and chemistry, which all varied with distance from lesions. Mature scar borders at 14 d after SCI consisted primarily of newly proliferated astroglia with elongated cell processes that surrounded large and small clusters of inflammatory, fibrotic, and other cells. During scar formation from 5 to 14 d after SCI, cell processes deriving from different astroglia associated into overlapping bundles that quantifiably reoriented and organized into dense mesh-like arrangements. Selective deletion of STAT3 from astroglia quantifiably disrupted the organization of elongated astroglia into scar borders, and caused a failure of astroglia to surround inflammatory cells, resulting in increased spread of these cells and neuronal loss. In cocultures, wild-type astroglia spontaneously corralled inflammatory or fibromeningeal cells into segregated clusters, whereas STAT3-deficient astroglia failed to do so. These findings demonstrate heterogeneity of reactive astroglia and show that scar borders are formed by newly proliferated, elongated astroglia, which organize via STAT3-dependent mechanisms to corral inflammatory and fibrotic cells into discrete areas separated from adjacent tissue that contains viable neurons.