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Clifford, T.; Finkel, Z.; Rodriguez, B.; Joseph, A.; Cai, L. Glial Scar in Spinal Cord Injury. Encyclopedia. Available online: https://encyclopedia.pub/entry/42481 (accessed on 13 July 2025).
Clifford T, Finkel Z, Rodriguez B, Joseph A, Cai L. Glial Scar in Spinal Cord Injury. Encyclopedia. Available at: https://encyclopedia.pub/entry/42481. Accessed July 13, 2025.
Clifford, Tanner, Zachary Finkel, Brianna Rodriguez, Adelina Joseph, Li Cai. "Glial Scar in Spinal Cord Injury" Encyclopedia, https://encyclopedia.pub/entry/42481 (accessed July 13, 2025).
Clifford, T., Finkel, Z., Rodriguez, B., Joseph, A., & Cai, L. (2023, March 23). Glial Scar in Spinal Cord Injury. In Encyclopedia. https://encyclopedia.pub/entry/42481
Clifford, Tanner, et al. "Glial Scar in Spinal Cord Injury." Encyclopedia. Web. 23 March, 2023.
Glial Scar in Spinal Cord Injury
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This entry is adapted from the peer-reviewed paper 10.3390/cells12060853

Spinal cord injury (SCI) is a complex tissue injury resulting in permanent and degenerating damage to the central nervous system (CNS). Detrimental cellular processes occur after SCI, including axonal degeneration, neuronal loss, neuroinflammation, reactive gliosis, and scar formation. The glial scar border forms to segregate the neural lesion and isolate spreading inflammation, reactive oxygen species, and excitotoxicity at the injury epicenter to preserve surrounding healthy tissue. The scar border is a physicochemical barrier composed of elongated astrocytes, fibroblasts, and microglia secreting chondroitin sulfate proteoglycans, collogen, and the dense extra-cellular matrix.

spinal cord traumatic injury glial scar formation neural regeneration

1. Introduction

Spinal cord injury (SCI) is a debilitating affliction and results in a wide range of physical deficits, e.g., motor, sensory, and autonomic. Deficits include chronic pain, loss of bladder control, respiratory system strain, and loss of motor function causing immobility below the injury level. Recent studies have estimated that the overall global prevalence of SCI is 20.6 million cases and 250,000 to 500,000 patients each year suffer from SCI [1][2]. After SCI, a tissue scar forms surrounding the injury epicenter composed of glial and supporting cell types. However, many of these invading cell types also contribute to an inflamed, inhibitory microenvironment detrimental to neural regeneration [3]. This inhibitory microenvironment suppresses neural regeneration via secreted molecules that inhibit neuronal function or prevent axogenesis, e.g., chondroitin sulfate proteoglycans (CSPGs), Nogo-A, and myelin-associated glycoprotein (MAG) [4][5][6].

2. Cellular Events Immediately following Trauma

Immediately, the physical impact causes ischemia, mechanical damage, and physical ruptures in cell processes, organelles, and membranes [7]. Ischemia, in addition to damage-mediated ion channel defects and rapid calcium release via cell lysis, contributes to ionic imbalance at the injury epicenter [8][9]. Due to the mechanical damage, neurons often lose their function via axonal lesions and axons degrade and retract toward the soma, a process known as Wallerian degeneration [10][11]. Locally secreted inhibitory and inflammatory signals induce chemorepulsion of the axonal growth cone, resulting in an inability to generate new axons in the immediate area of the injury. Chronic demyelination of axons occurs primarily at 24 h post-injury and remains prevalent up to one year post-injury [12], a process by which immune cells continuously attack newly synthesized myelin, inhibiting neuronal function. In conjunction, oligodendrocytes lose their function due to mechanical processes and somal cleavage resulting in an inhibitory environment for functional axon formation. Myelin-associated molecules are dispersed around the injury site from injured axons and oligodendrocytes. These molecules, primarily MAG, oligodendrocyte myelin glycoprotein (OMgp), and Nogo-A, are all known inhibitors of neural, axonal regeneration, and plasticity, and persist during scar formation and maturation [4][6][13]. Surviving cells attempt remyelination, but recovery is chronically diminished due to the inhibitory microenvironment and physical barrier generated by astrocytes and supporting scar border cells [6]. A cascade of cellular/molecular events occur resulting in mass cell death, spreading inflammation, and an inhibitory microenvironment [14][15][16]. Cell membranes are lysed during the injury impact, inducing a spike of depolarization in local cells. The depolarization of cell membranes and the dysregulation of homeostatic processes results in the release of many different types of cell signals [16]. This local damage signaling cascade and ischemia-initiated damage results in mass ATP release by cells and serves as the primary signaling molecule to initiate glial scar formation [17][18][19]. P2 receptors are present on oligodendrocytes, astrocytes, and oligodendrocyte progenitor cells (OPCs), inducing the first instances of mobility around the injury lesion [20][21]. These initial cellular events also lead to the expression of a variety of signals, e.g., proapoptotic, necroptotic, ferroptotic, proinflammatory, anti-inflammatory, and many signals that serve cell-recruiting functions [22][23][24]. Chemokines, cytokines, alarmins, and damage-associated molecular patterns (DAMPs) initiate the reactive response in cellular components of the scar and define the pathology of glial scar formation via the recruitment of various cell types, e.g., astrocytes, fibroblasts, microglia, neural stem/progenitor cells (NSPCs), fibroblasts, macrophages, and invading immune cells [3][16].

3. Glial Scar Formation

The glial scar is composed of various cell types: astrocytes, fibroblasts, NSPCs, microglia, macrophages, and immune cells (Figure 1). Glial scar formation is induced by a combination of cell signals to the surrounding area following injury and develops for months after SCI [25][26][27][28][29]. These signals induce a heterogenous population of glial cells, primarily resident astrocytes, into a state of reactive gliosis. During reactive gliosis, astrocytes become activated and exhibit major differences in soma size, cell location, morphology, enhanced proliferation, and transcriptional profile [21][30][31][32]. Astrocytes translocate and congregate around the lesion site while expressing filament proteins such as glial fibrillary acidic protein (GFAP), Nestin, and Vimentin to stabilize the newly formed astrocytic structure [5][30]. Transposed astrocytes proliferate to form a physical barrier, a process mediated by STAT-3 signaling and leucine zipper-bearing kinase (LZK) expression [25][33][34]. Reactive astrocytes secrete molecular signals, including the yes-associated protein (YAP), CCL2, and Csf2, that contribute to the recruitment of other cell types, primarily immune cells, while physically ensnaring fibroblasts by 7 days post injury (dpi) [35][36][37][38]. Fibroblasts and astrocytes produce extracellular matrix (ECM) molecules to stabilize the glial scar, e.g., CSPGs, fibronectin, laminin, collagen, and proteoglycans from fibroblasts, and provide shape and stability [5][30][39][40][41]. After 1–2 weeks, astrocytic proliferation stops, effectively representing glial scar maturation. A phase change to the chronic state is also emphasized by the glial process shift from perpendicular to parallel and fosters stable and compact tissue formation mediated by STAT-3 signaling [25][34][42].
Cells 12 00853 g001
Figure 1. Schematic diagram illustrating glial scar formation. (A) Formation of the lesion and scar during the acute phase of SCI. (B) Formation of the fibrotic tissue and glial scar during the chronic phase of SCI. (C) White box region in B detailing the layers of the glial scar: I. astrocytes, II. microglia, III. secreted stromal ECM/CSPGs, IV. fibroblasts, and V. stromal ECM/CSPGs and penetrating macrophages.
Fibroblast populations are present in the basal laminae and parenchyma of the brain and are distributed consistently throughout the spinal cord. After SCI, fibroblasts become activated to proliferate and migrate toward the lesion by 3 dpi [38][43][44]. This cell population is bolstered by nearby pericytes which undergo differentiation into stromal fibroblasts, a process which peaks at 2-weeks post-injury [29][38]. The primary function of fibroblasts after SCI is to produce stromal ECM molecules and fortify the glial scar structure, as well as provide inhibitory signaling to generate a physicochemical barrier that protects the injured tissue from invading species. This molecular activity results in fibrosis and the formation of a clear “fibrotic scar” medial to the glial layer, composed of fibroblasts and surrounding stromal ECM [29]. In clinically relevant contusion SCI, fibroblast deposition around the injury site increases dramatically by 5 dpi and peaks at 7 dpi. In contrast, in dorsal hemisection SCI, fibroblast deposition peaks at 9–14 dpi [45]. The fibrotic aspect of the SCI scar is seen as an absolute barrier to neural regeneration and is a key motivator for many therapeutic approaches [46].
Native and invading immune cells contribute to inflammatory statis, a defining aspect of the glial scar’s pathology. Microglia constitute the primary immune response to general CNS injury and work in tandem with macrophages as the major reactive cell type immediately after SCI [38]. The roles of microglia and macrophages often overlap due to their common lineage, morphological characteristics, molecular protein markers, and genes expressed after injury. It is accepted, however, that microglia subtypes perform a diverse variety of functions in the healthy and injured spinal cord [3][47][48]. These processes include reactive phagocytosis, the recruitment of immune cells, antigen processing, and the regulation of the pro-inflammatory condition [16]. Within 24 h, the majority of immune cell types are recruited to the injury site, including monocyte-derived or microglia-derived macrophages, leukocytes, T cells, and B cells [3]. These populations induce reactivity and a pro-inflammatory state around the glial scar via DAMPs and inflammatory cytokines [47]. Microglia possess the lowest threshold for reactivity and initiate glial scar formation via IGF-1 release stimulating astrocyte reactivity and proliferation, as well as improving scar formation itself via the downregulation of astrocytic P2Y1 receptors [17][18][21][47]. Microglia persist around the injury site for up to 6 months and contribute to the chronic state and neuropathic pain [47]. Microglia also maintain cellular crosstalk with the major cell types in the glial scar and are thus a vital cell type to gain understanding of for SCI therapeutic development [21][48][49][50][51][52].
Macrophages play an integral role in scar development and recovery by performing a variety of functions including notable phagocytosis of cell debris around the injury site [48][52]. Monocytes are recruited to the injury by astrocytes during the acute phase via chemokine/cytokine release, e.g., CCL2, CCL5, and CXCL8 [53][54][55], and differentiate into macrophage subtypes: pro-inflammatory (M1) and anti-inflammatory (M2). Astrocytes induce macrophage polarization and mobility toward the lesion via chemotaxis [53]. In the subacute SCI phase, M1 macrophages upregulate astrocyte activation to induce glial scar formation while M2 macrophages secrete TGF-β in vitro [56][57]. Crosstalk between macrophages and other common glial-scar-forming cell types allows M2 macrophages to polarize astrocytes and direct glial scar contributions [55][57]. Macrophages and fibroblasts migrate to the neural lesion and contribute to scar formation up to 14 dpi. However, after macrophages are cleared from the scar, the density of the fibrotic region is significantly reduced/disrupted, suggesting a role of macrophages to manipulate fibroblast migration and position [38][58].
Immediately after SCI, NSPC populations transition from quiescent to the activated state, e.g., neural stem cells, ependymal progenitors, and OPCs/NG2 polydendrocytes [59]. Activated NSPCs proliferate and differentiate into glial lineage cells and contribute to the formation of the glial scar border [22][27][28]. Multipotent asymmetric division allows NSPCs and progeny to differentiate into the glial cells of the scar border in synchrony with recruited resident astrocytes. Ependymal cells have been shown to possess stem-like qualities after neural injury such as self-renewal and multipotency [60][61]. Ependymal cells line the central canal of the spinal cord and guide adjacent cerebrospinal fluid (CSF) via cilia into the lateral ventricles of the brain. Ependymal cells contribute to few clinical injury types due to low migratory capacity even in an activated state. However, in stab and contusion SCI, ependymal cells become activated, revert to a stem-cell-like state, and contribute to astrocyte population due to central canal damage [59]. Ependymal progenitors are thus a popular target for regenerative therapies.
Oligodendrocyte progenitor cells (OPCs) differentiate into oligodendrocytes and Schwann cells to remyelinate neurons and repair damaged sheaths [26][27]. OPCs also express NG2, a proteoglycan responsible for the trapping, congregation, and efficient myelination of many neurons [28][37]. NG2+ polydendrocytes are a population containing OPCs, macrophages, and pericytes displaying stem-cell-like characteristics of self-renewal and multipotency before and after SCI [62][63][64]. This NSPC population is spatially distributed in a checker-like pattern throughout the mammalian spinal cord. Thus, this population contributes to the glial scar of various SCI types and grades due to distribution and migratory capacity [59]. NG2 polydendrocytes natively possess qualities of their differentiated progeny, e.g., hypertrophy and secretion of inhibitory molecules that inhibit axogenesis. Furthermore, this population can form functional synapses with neurons in the immediate vicinity. NG2 polydendrocytes provide a potential target for therapeutics due to NSPC qualities and interactions with crucial cell types for synaptic transmission and glial scar formation [37][62].

4. Positive and Negative Effects of the Glial Scar

The nature of the glial scar in the context of regeneration after SCI is highly debated in the field [36][65][66]. While the scar may inhibit regeneration through the lesion, it also preserves the viable tissue surrounding the lesion [67]. Glial scar formation results from a combination of complex processes including inflammation, reactive gliosis, apoptosis, autophagy, and others [68][69][70]. To design effective therapeutics, the potential consequences of manipulation of each process must be carefully considered. In the field, two strategies to target the glial scar have been developed: targeting glial scar formation and targeting aspects of the established scar. Positive and negative effects of the glial scar in the injured spinal cord have been extensively explored (Table 1). Collectively, these observations have fostered the development of research strategies to target scar formation or components of the established scar as the next stage of SCI therapeutic development. Moreover, a combinatorial approach may be the most effective to establish a treatment that is optimal.
Table 1. Positive and negative effects of the glial scar.
Positive Effects: References:
Uptakes excess glutamate preventing chronic glutamate neurotoxicity [70][71]
Macrophages improve overall tissue quality through removal of cell debris [43][55][57]
Prolonged tissue repair signaling [16][36][49]
Maintains body’s natural excitation/inhibition ratio; helps prevent irregular signaling [45][72][73]
Physical barrier to protect remaining functional tissue [14][29][37]
Negative Effects:  
Non-resolving auto-immune response that leads to fueling fibrosis; over stimulation of inflammation leads to damaged surrounding tissues [16][74]
Over stimulation of inflammation leads to damaged surrounding tissues [16][50][75]
Inhibits differentiation of OPCs [26][76]
Inhibits axogenesis, plasticity of the neuron, and myelin generation [4][5][6][13][77]
Physical barrier making transplanted/endogenous cell migration difficult [29][35][45][78]
Excessive production of free radicals, reactive oxygen species (ROS), and glutamate, as well as ion imbalance [14][79][80][81]

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Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Tanner Clifford
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Zachary Finkel
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Brianna Rodriguez
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Adelina Joseph
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Li Cai
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Update Date: 24 Mar 2023
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