Portrait of glial scar in neurological diseases

Abstract

Fibrosis is formed after injury in most of the organs as a common and complex response that profoundly affects regeneration of damaged tissue. In central nervous system (CNS), glial scar grows as a major physical and chemical barrier against regeneration of neurons as it forms dense isolation and creates an inhibitory environment, resulting in limitation of optimal neural function and permanent deficits of human body. In neurological damages, glial scar is mainly attributed to the activation of resident astrocytes which surrounds the lesion core and walls off intact neurons. Glial cells induce the infiltration of immune cells, resulting in transient increase in extracellular matrix deposition and inflammatory factors which inhibit axonal regeneration, impede functional recovery, and may contribute to the occurrence of neurological complications. However, recent studies have underscored the importance of glial scar in neural protection and functional improvement depending on the specific insults which involves various pivotal molecules and signaling. Thus, to uncover the veil of scar formation in CNS may provide rewarding therapeutic targets to CNS diseases such as chronic neuroinflammation, brain stroke, spinal cord injury (SCI), traumatic brain injury (TBI), brain tumor, and epileptogenesis. In this article, we try to describe the new portrait of glial scar and trending of research in neurological diseases to readers.

Keywords: fibrosis; glial scar; inflammation; neurological diseases.

Figure 1.

Reactive astrocytes in the formation of glial scar and where they form. The astrocyte goes through tremendous changes including hypertrophy, migration, proliferation, gene expression, and functional alternations, depending on the distance from the lesion core and the severity of the damage in many CNS pathologies. Astrocytic proliferation, migration, and activation are involved in glial scar formation in a coordinating manner. As for induction of reactive astrocytes leading to glial scar formation, several studies showed that some neural progenitors, such as ependymal cells and NG2+ cells, are involved in gliogenesis in this process at the limited brain regions. It is reported that the forming of glial scar involves these phenotypic alternations which is regulated by many different signal mechanisms. The key molecules (including AQP, CX30, CX43, ET-1, TGF-β1, and MMP9) play pivotal roles in regulating the induction of glial scar formation.

Figure 2.

The key transcription factors regulating the glial scar formation in CNS pathologies. The induction of glial scar formation is stimulated by a variety of signaling molecules (such as IL-1, IL-6, CNTF, ET-1, EGF, FGF2, TGF-β1, BMPs, and LIF) from the tissue near the lesion. These signaling molecules play crucial roles in activating the transcription factors that regulate the astrocytic hypertrophy, migration, proliferation, gliogenesis, and inflammation, which promotes the formation of glial scar. IL: interleukin; LIF: leukemia inhibitory factor; CNTF: ciliary neurotrophic factor; ET-1: endothelin-1; EGF: epidermal growth factor; FGF2: fibroblast growth factor-2; TGF-β1: transforming growth factor-b1; BMP: bone morphogenic protein; STAT3: signal transducer and activator of transcription 3; Sp1: specificity protein 1; OLIG2: oligodendrocyte transcription factor 2; SMAD: Sma- and Mad-related protein; NFκB: nuclear factor-kappa B.