The diversity and disparity of the glial scar

Abstract

Injury or disease to the CNS results in multifaceted cellular and molecular responses. One such response, the glial scar, is a structural formation of reactive glia around an area of severe tissue damage. While traditionally viewed as a barrier to axon regeneration, beneficial functions of the glial scar have also been recently identified. In this Perspective, we discuss the divergent roles of the glial scar during CNS regeneration and explore the possibility that these disparities are due to functional heterogeneity within the cells of the glial scar—specifically, astrocytes, NG2 glia and microglia.

Influence of white matter injury on gray matter reactive gliosis upon stab wound in the adult murine cerebral cortex

“…Traumatic injury in the central nervous system (CNS) has deleterious consequences given the limited capacity for functional recovery. Glial cells are key in the first steps of wound closure, but also contribute to later scar formation (Adams & Gallo, ; Anderson et al, ; Burda & Sofroniew, ; Dimou & Götz, ; Liddelow et al, ). Scar formation inhibits axonal regeneration, like that observed after spinal cord injury (Burda & Sofroniew, ; Silver, Schwab, & Popovich, ), but also results in dysfunctional tissue and epileptic foci in the brain (Heinemann, Kaufer, & Friedman, ).…”

“…To which extent these also apply, however, to the brain is less clear. Indeed, regional differences may well explain sometimes opposing findings (Adams & Gallo, ). Prominent differences have been observed between microglia and macrophage reactions between spinal cord and brain traumatic injury (TBI) (Donnelly & Popovich, ; Silver et al, ; Trivedi, Olivas, & Noble‐Haeusslein, ) and also the fibrotic/pericyte‐derived scar differs in traumatic brain injury (Fernandez‐Klett & Priller, ; Goritz et al, ).…”

Concepts toward directing human astroplasticity to promote neuroregeneration

“…However, the extent to which this reaction and extracellular signaling are transformed by specific insults—including traumatic brain and spinal cord injury (SCI) (Burda et al, ; Okada et al, ), ischemic and hemorrhagic stroke (Scimemi, ), neurodegeneration (Ben Haim et al, ), multiple sclerosis (Ponath et al, ), cancer (Guan et al, ), and pathogen‐mediated inflammation (Skaper et al, )—has been difficult to characterize. This obscurity is due in part to astrocytes’ dynamic and diverse transitions between cellular states (Liddelow and Barres, ; Adams and Gallo, ; Tran et al, ), which can have either beneficial or detrimental impact depending on the type and severity of stimuli. The formation of astroglial scars after injury, for example, is a type of state transition reminiscent of fibrosis and comprised of scar astrocytes.…”

NG2 Glia: Novel Roles beyond Re-/Myelination

“…Thus, beyond their role in myelin repair and glial scar formation [205], depending on the circumstances, NG2 glia have been observed either to limit CNS damage or to actively contribute to neuroinflammation/neurotoxicity, as also shown in Amyotrophic Lateral Sclerosis models [206]. To further increase the complexity of this scenario, consistent with previous findings [207,208], in vivo two-photon imaging analyses revealed an assortment of distinct NG2 glia reactions to injury, with some cells starting migration toward the lesion site, others entering cell cycle, and others displaying only hypertrophy and morphological changes [31,86].…”