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Portrait of Glial Scar in Neurological Diseases

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Portrait of Glial Scar in Neurological Diseases IJI0010.1177/2058738418801406International Journal of Immunopathology and PharmacologyWang et al. 801406letter2018 Letter to the Editor International Journal of Immunopathology and Pharmacology Portrait of glial scar in neurological Volume 31: 1–6 © The Author(s) 2018 Article reuse guidelines: diseases sagepub.com/journals-permissions DOI:https://doi.org/10.1177/2058738418801406 10.1177/2058738418801406 journals.sagepub.com/home/iji Haijun Wang1, Guobin Song1, Haoyu Chuang2,3,4, Chengdi Chiu4,5, Ahmed Abdelmaksoud1, Youfan Ye6 and Lei Zhao7 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 Date received: 24 April 2018; accepted: 28 August 2018 Introduction tissue, most of the patients who have neurological disorders suffer from the loss of normal sensorimotor Scar formation after injury or disease leaves per- function which means losing their basic life guar- manent deficits for patients, especially in central antee and their fundamental life support abilities.1 nervous system (CNS) diseases. Since scar for- Furthermore, with the reduction in quality of life mation is the most common response in damaged 1 Department of Neurosurgery, Union Hospital, Tongji Medical 7 Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, College, Huazhong University of Science and Technology, Wuhan, Hubei, China Hubei, China 2 Department of Neurosurgery, Tainan Municipal An-Nan Hospital- Corresponding authors: China Medical University, Tainan, Taiwan, China Youfan Ye, Department of Ophthalmology, Union Hospital, Tongji 3 Department of Neurosurgery, China Medical University Beigang Medical College, Huazhong University of Science and Technology, Hospital, Beigang, Taiwan, China Wuhan, 430022, China. 4School of Medicine, China Medical University, Taichung, Taiwan, China Email: [email protected] 5 Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, China Lei Zhao, Department of Infectious Diseases, Union Hospital, Tongji 6 Department of Ophthalmology, Union Hospital, Tongji Medical Medical College, Huazhong University of Science and Technology, College, Huazhong University of Science and Technology, Wuhan, Wuhan, 430022, China. Hubei, China Email: [email protected] Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). 2 International Journal of Immunopathology and Pharmacology 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. and the increase in the cost of care, patients who expression of intermediate filament (IF) proteins, cannot live independently are more likely to expe- and functional changes. Astrocytic activation is rience depression after survival of neurological also accompanied by the production of various diseases.1 cytokines, chemokines, growth factors, and neuro- The consequence of scar formation in the CNS trophic factors. is usually considered more detrimental than that The astrocytes near the lesion undergo tremen- in the peripheral organs because of impaired neu- dous changes, including changes in morphology, ral function recovery.2 Moreover, activated gene expression, proliferation, and function, which inflammatory cells can also induce secondary are often collectively described as reactive astro- damage to intact cells and can impair post-injury gliosis. Many features of astrocytes are shared synaptic regeneration. However, fibrotic scars among various diseases, while astrocytic responses provide perineuronal nets for both synaptic matu- are not the same in all diseases due to the differ- ration and CNS plasticity by forming a dense ences in specific diseases. extracellular matrix (ECM) to provide extracel- lular space and by inducing adult neurogenesis, Signal molecules of activated respectively. Accumulating data suggest that the astrocytes in glial scar formation predominance of a detrimental or beneficial action of glial scar formation after neural diseases Signal molecules in coordination play crucial roles is considered to depend on the microenvironment in astrocytes for glial scar formation after damage at the injury site and the types of brain disorders occurs (Figure 1). Some of the key molecules that and the severity.3 are involved in astrocytic hypertrophy, prolifera- tion, migration, and gliogenesis orchestrate the for- mation of glial scars. The activated form of astrocytes in The cytoskeletons of astrocytes are highly pathologies changeable; they have a strong potential to quickly Astrocytic activation is the activated form of astro- remodel themselves to cooperate with the normal cytes in response to brain disorders. Reactive astro- development of morphogenesis and tissue injury.4 cytes are characterized by hypertrophy, high IF proteins are a part of the structure of cytoskeletal Wang et al. 3 to degrade the protein in the ECM.5 The production of MMP9 is stimulated by endothelin-1 (ET-1), transforming growth factor (TGF)-β1, and throm- bin. When MMP9 is inhibited in mice with spinal cord injury, astrocytic migration and glial scar for- mation are inhibited. Aquaporin (APQ) water channels, which facilitate cell migration, are highly expressed in cell plasma membranes. AQP4 is expressed primarily in the astrocytic end-feet.6 In AQP4-knockout mice, the migration of reactive astrocytes is slowed. This result suggests that AQP4 activities are important to astrocytic migra- tion too. Proliferation is another crucial factor for astro- Figure 2. The key transcription factors regulating the glial cytic accumulation in damaged parts of CNS that scar formation in CNS pathologies. leads to glial scar formation. In neurological dis- The induction of glial scar formation is stimulated by a variety of eases, the neural stem cells and progenitors can 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 transform into neurons and glial cells. Recent stud- molecules play crucial roles in activating the transcription factors that ies have proved that reactive astrocytes in the glial regulate the astrocytic hypertrophy, migration, proliferation, gliogen- esis, and inflammation, which promotes the formation of glial scar. IL: scar are derived from glial progenitors. NG2 cells interleukin; LIF: leukemia inhibitory factor; CNTF: ciliary neurotrophic can differentiate into proliferating reactive astro- factor; ET-1: endothelin-1; EGF: epidermal growth factor; FGF2: fibro- cytes in brain injuries, and ependymal cell precur- blast growth factor-2; TGF-β1: transforming growth factor-b1; BMP: bone morphogenic protein; STAT3: signal transducer and activator sors generate scar-forming astrocytes in spinal of transcription 3; Sp1: specificity protein 1; OLIG2: oligodendrocyte cord injury and stroke.7 transcription factor 2; SMAD:
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