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

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.

Cells transplanted onto the surface of the glial scar reveal hidden potential for functional neural regeneration

“…4 A and B), reminiscent of gliaguided migration of newborn neurons in the developing cortex (19,20). Astrocytes at the lesion appeared to lose their stellate morphology and to adopt overlapping, elongated morphologies (21) (Fig. 4C).…”

The 3 Rs of Stroke Biology: Radial, Relayed, and Regenerative

“…Reactive astrocytes are not one homogenous type of cell but instead display distinct morphological and functional properties in zones that extend away from the infarct or central nervous system injury. This has been best detailed in the injured spinal cord and in normal brain, where distinct morphologies of reactive astrocytes indicate likely different zones of tissue repair and recovery [70], or of distinct circuit function [71]. In stroke, distinct types of reactive astrocytes are also present.…”

Stochastic nanoroughness modulates neuron–astrocyte interactions and function via mechanosensing cation channels

“…Dynamic changes to astrocyte-neuron interaction mediated by changes to distal astrocytic processes are known to influence neuron-astrocyte plasticity (15). Although astrocytes are generally stationary cells that provide a supportive network for neuronal cells and synapses, migratory and proliferating astrocytes have been observed in glial scarring, an environment with diminished neuronal function (43,44). In this study, an altered cellular environment in the form of nanotopography was shown to affect astrocyte biophysical attributes (shape and roughness) so as to alter their interaction with neurons.…”