Glial scar formation (gliosis) is a reactive cellular process involving
astrogliosisthat occurs after injury to the Central Nervous System. As with scarringin other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system. Although the glial scar does a good job at controlling and suppressing further physical damage, it does have important caveats to neuroregeneration. Particularly, many neuro-developmental inhibitormolecules are secreted by the cells within the scar that prevent complete physical and functional recovery of the central nervous system.
As an example, consider
paralysis. After the physical injury that severs or damages the spinal cord, the formation of the glial scar partly explains why the patient is not able to fully recover functional normalcy.
The glial scar is composed of several components briefly discussed below.
astrocytesare the main cellular component of the glial scar. Stichel CC, Muller HW (1998). "The CNS lesion scar: new vistas on an old regeneration barrier." Cell Tissue Research 194:1-9. ] After injury, astrocytes undergo morphological changes and increase synthesis of glial fibrillary acidic protein(GFAP). GFAP is an important intermediate filamentprotein that allows the astrocytes to begin sythesizing more cytoskeletal supportive structures and extend pseudopodia. Ultimately, the astrocytes form a dense web of their plasma membrane extensions that fills the empty space generated by the dead or dying neuronal cells (a process called astrogliosis). The heavy proliferation of astrocytes also modifies the extracellular matrixsurrounding the damaged region by secreting many molecules. Such molecules include laminin, fibronectin, tenascin C, and proteoglycans. These molecules are important modulators of neuronal development; they therefore are partially the cause of the inhibitory characteristics of the glial scar.
Another important caveat of the astrocytic response to Central Nervous System injuries is its heterogeneity. Particularly, the response of the astrocytes to the injury varies on factors such as the nature of the injury, the proximity to the lesion, and the microenvironment at the injury location. David S, Ness R. (1993). "Heterogeneity of reactive astrocytes." In: Fedoroff S (ed) Biology and pathology of astrocyte-neuron interactions. Plenum Press, New York, pp 303-312. ] Fernaud-Espinosa I, Nieto-Sampedro N, Bovolenta P. (1993). "Differential activation of microglia and astrocytes in aniso- and isomorphic gliotic tissue." Glia 8: 277-291 ] Further, the reactive astrocytes in the immediate vicinity of the injury usually show increased changes in gene expression, compounding the response of astrocytes and contributing to the heterogeneity. Particularly, the astrocytes closest to the lesion usually secrete more molecules into the extracellular matrix.Stichel CC, Muller HW (1998). "The CNS lesion scar: new vistas on an old regeneration barrier." Cell Tissue Research 194:1-9. ]
Microgliaare the second most prominent cell type of the glial scar. They are the nervous system analog of immune system macrophages. Microglia cells rapidly activate around an injury region and secrete several cytokines, bioactive lipids, coagulation factors, reactive oxygen intermediates, and neurotrophic factors. Elkabes S, DiCicco-Bloom EM, Black IB (1996). "Brain microglia/ macrophages express neurotrophins that selectively regulate microglial proliferation and function." Journal of Neuroscience 16: 2508- 2521 ] The expression of these molecules depends on the location of the microglial cells relative to the injury, with the cells closest to the injury secreting the largest amount of such biologically active molecules.
Endothelial cells and fibroblasts
The various biologically active molecules secreted by microglia stimulate and recruit
endothelial cellsand fibroblasts. These cells help stimulate angiogenesisand collagen secretion into the injured area. Ultimately, the amount of capillaries extended into the injured area is twice that of uninjured central nervous system regions. Jaeger CB, Blight AR (1997). Spinal compression injury in guinea pigs: structural changes of endothelium and its perivascular cell associations after blood-brain barrier breakdown and repair. ExperimentalNeurology 144: 381-399 ]
The basal membrane is a
histopathological extracellular matrixfeature that forms at the center of injury and partially covers the astrocytic processes. It is composed of three layers with the basal laminaas the prominent layer. Molecularly, the basal membrane is created by glycoprotein and proteoglycan protomers. Further, two independent networks are formed within the basal membrane by collagen IV and lamininfor structural support. Other molecular components of the basal membrane include fibulin-1, fibronectin, entactin, and hepparan sulfate proteoglycan perlecan. Ultimately, the astrocytes attach to the basal membrane, and the complex surrounds the blood vessels and nervous tissue to form the initial wound covering.Stichel CC, Muller HW (1998). "The CNS lesion scar: new vistas on an old regeneration barrier." Cell Tissue Research 194:1-9. ]
The ultimate function of the glial scar is to reestablish the physical and chemical integrity of the Central Nervous System. This is done by generating a barrier across the injured area that seals the nervous / non-nervous tissue boundary. This also allows for the regeneration of the selective barrier to prevent further microbial infections and spread of cellular damage. Moreover, the glial scar stimulates revasularization of blood capillaries to increase the nutritional, trophic, and metabolic support of the nervous tissue.Stichel CC, Muller HW (1998). "The CNS lesion scar: new vistas on an old regeneration barrier." Cell Tissue Research 194:1-9. ]
The glial scar unfortunately also prevents neuronal
axonextensions. The central nervous system neuron's axons begin to sprout and extend across the injury site in an attempt to repair the damage. However, the scar prevents these extensions via physical and chemical means. Astrocytes are able to form a dense network of gap junctionsthat generates a physical barrier to axon extensions. Further, the astrocytes secrete several growth-inhibitory molecules that chemically prevent axonal extensions. Moreover, the basal membrane component is expected to generate an additional physical and chemical barrier to axonal extensions. Stichel CC, Muller HW (1998). "The CNS lesion scar: new vistas on an old regeneration barrier." Cell Tissue Research 194:1-9. ]
Primary scar molecular inducers
The formation of the glial scar is a complex process that is still being currently investigated. Several main classes of molecular triggers for gliosis have been identified and are briefly discussed below.
Transforming growth factor β (TGF-β)
Two neuronally-important subclasses of
transforming growth factorfamily of molecules are TGFβ-1 and TGFβ-2 that directly stimulate astrocytes, endothelial cells, and macrophages. TGFβ-1 has been observed to increase immediately after injury to the central nervous system, whereas TGFβ-2 expression occurs more slowly near the injury site. Further, TGFβ-2 has been shown to stimulate growth-inhibitory proteoglycans by astrocytes. Asher RA, "et al." (2000). "Neurocan is upregulated in injured brain and in cytokine-treated astrocytes." Journal of Neurosciemce 20, 2427–2438. ] Experimental reduction of TGFβ-1 and TGFβ-2 has been shown to partially reduce glial scarring. Moon LDF, & Fawcett JW. (2001). "Reduction in CNS scar formation without concomitant increase in axon regeneration following treatment of adult rat brain with a combination of antibodies to TGFβ1 and β2." European Journal of Neuroscience 14, 1667–1677. ]
Interleukins are another potential family of scar-inducing cellular messengers. Particularly, interleukin-1, a protein produced by mononuclear phagocytes, helps to initiate the inflammatory response in astrocytes, leading to reactive astrogliosis and the formation of the glial scar. Giulian D, "et al." (1988). "Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization." Journal of Neuroscience 8, 2485–2490. ] Silver J, & Miller J. (2004). "Regeneration beyond the glial scar." Nature Reviews Neuroscience. 5(2): 146-156. ]
cytokinefamily of glial scar inducers include interferon-γ (IFNγ) and fibroblast growth factor 2 (FGF2). IFNγ has been shown to induce astrocyte proliferation and increase the extent of glial scarring in injured brain models. Yong VW "et al." (1991). "γ-Interferon promotes proliferation of adult human astrocytes "in vitro" and reactive gliosis in the adult mouse brain "in vivo"." PNAS USA 88, 7016–7020. ] Further, FGF2 production has been observed to increase after injury in the brain and spinal cord, and it has been shown to also increase astrocyte proliferation in "in vitro" conditions. Lander C, "et. al" (1997). "A family of activity-dependent neuronal cell-surface chondroitin sulfateproteoglycans in cat visual cortex." Journal of Neuroscience 17, 1928–1939. ] Mocchetti I, "et al." (1996). "Increased basic fibroblast growth factor expression following contusive spinal cord injury." Experimental Neurology 141, 154–164. ]
Ciliary neurotrophic factor (CNTF)
Ciliary neurotrophic factor (CNTF) is a cytosolic protein that is not secreted. CNTF has been shown to promote the survival of neuronal cultures "in vitro", and it can also act as a differentiator and
trophic factoron glial cells. Further, CNTF has been previously shown to affect the differentiation of glial precursor cells "in vitro"; however, the influence of CNTF in "in vivo" conditions has only recently been determined. Winter "et al." generated transgenic mice that over expressed CNTF. These and normal mice that had CNTF levels artificially elevated via injection were subjected to neuronal da
4 (a known neuronal degenerative factor) was injected intranasally in the
olfactory epithelium. Afterwards, the olfactory bulbwas studied to determine the amount of glial scar formation; a Northern blotwas performed to determine GFAP mRNAlevels, markers of glial scar formation. It was determined that mice with elevated ciliary neurotrophic factor increased their mRNA levels (and therefore GFAP production) two-fold. It was therefore hypothesized that CNTF has at least a partial role in generating the glial scar during central nervous system damage. Winger, CG, "et al.." (1995). "A role for ciliary neurotrophic factor as an inducer of reactive gliosis, the glial response to central nervous system injury." Proc. Natl. Acad. Sci, USA, 92, 5865 - 5869.]
Upregulation of nestin intermediate filament protein
Nestinis an intermediate filament(IF) protein that assists with IF polymerization and macromolecule stability. Intermediate filaments are an integral part of cell motility, a requirement for any large migration or cellular reaction. Nestin is normally present during central nervous system(CNS) development and reactivates during minor stresses to the CNS. However, Frisen "et al." determined that nestin is also upregulatedduring severe stresses such as lesions which involve the formation of the glial scar. Mid-thoracic spinal cord lesions, optic nervelesions, and sciatic nervelesions were performed on rat models. Immunohistochemicaltests using antibodies for nestin showed a marked increase within the first 48 hours in the spinal cord and optic nerve lesion models. Further, nestin upregulation was shown to last for up to 13 months post-injury. However, peripheral nerve lesion in the sciatic nerve did now show an increase in nestin synthesis. Therefore, nestin upregulation is a major cause of the recruitment of the large amount of cells observed in CNS glial scarring. Frisen, J. (1995). "Rapid, widespread, and long lasting induction of nestin contributes to the generation of glial scar tissue after CNS injury." The Journal of Cell Biology, 131(2): 453-464.]
uppression of glial scar formation
Several techniques have been devised to suppress the formation of the glial scar. Such techniques can be combined with other neuroregeneration techniques to help with functional recovery.
Olomoucine, a purine derivative, is a
cyclin-dependent kinase(CDK) inhibitor. CDK is a cell-cycle promoting protein; it and other pro-growth proteins are abnormally activated during glial scar formation. Such proteins can increase astrocyte proliferation and can also lead to cell death, furthering cellular damage at the neuronal lesion site. Administration of olomoucine peritoneally has been shown to suppress CDK function. Further, olomoucine has been shown to reduce neuronal cell death, reduce astroglial proliferation (and therefore reduce astrogliosis), and increase GAP-43 expression, a useful protein marker for neurite growth. Moreover, reduced astrocyte proliferation decreases expression of chondroitin sulphate proteoglycans(CSPGs), major molecules associated with the inhibitory neuroregeneration environment of glial scars. Tian D, "et al." (2006). "Suppression of Astroglial Scar Formation and Enhanced Axonal Regeneration Associated with Functional Recovery in a Spinal Cord Injury Rat Model by the Cell Cycle Inhibitor Olomoucine." Journal of Neuroscience Research, 84: 1053-1063. ]
Recent work has also shown that olomoucine suppresses
microgliaproliferation within the glial scar environment. This is particularly important because microglia play an important role in the secondary damage following spinal cord lesion, during the formation of the glial scar. Microglial cells are activated via various pro-inflammatory cytokines (some discussed above). Rat spinal cord injury models have shown remarkable improvements after the administration of olomoucine. One hour-post administration, olomoucine suppressed microlgial proliferation, as well as reduced the tissue edemanormally present during the early stages of glial scar formation. Further, 24 hours post-administration, a reduction in concentration of activation cytokine interleukin-1β was observed. Additionally, the administration of olomoucine has also been shown to decrease neuronal cell death. Tian D., "et.al." (2007). "Cell cycle inhibition attenuates microglia induced inflammatory response and alleviates neuronal cell death after spinal cord injury in rats." Brain Research, 1135: 177-185.]
Inhibition of phosphodiesterase 4 (PDE4)
Phosphodiesterase 4 is a member of the
phosphodiesterasefamily of proteins that cleave phosphodiesterbonds. This is an important step in degrading cyclic adenosine monophosphate(cAMP), a major intracellular signaling molecule; conversely, blocking PDE4 will increase cAMP. Increased intracellular cAMP levels in neurons have been previously shown to entice them to grow. Neumann, S., "et al." (2002). "Regeneration of Sensory Axons within the Injured Spinal Cord Induced by Intraganglionic cAMP Elevation." Neuron 34, 885–893.] Nikulina "et al." in 2004 showed that administration of " rolipram", a phosphodiesterase 4 inhibitor, can increase cAMP levels in neurons. This is partially possible because rolipram is sufficiently small to pass through the blood-brain barrierand immediately begin to catalyze reactions in neurons. In two week post-injury animal models, rolipram was administered for 10 consecutive days. Considerable axon growth was observed with a reduction in glial scarring. The specific mechanism reducing glial scarring in this case is currently unknown, but possible mechanisms include axonal extensions that physically prevent reactive astrocytes from proliferating, as well as chemical signaling events to reduce reactive astrogliosis. Nikulina, E. "et al." (2004). "The phospodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery." Proc Natl Acad Sci U.S.A. 101(23): 8786–8790.]
Ribavirinis a purine nucleoside analogue that is generally used as an anti-viral medication. However, it has also been shown to decrease the amount of reactive astrocytes. Daily administration for at least 5 days on rat brain injury models was shown to significantly decrease the number of reactive astrocytes. Pekovic, S., "et al." (2006). "Downregulation of glial scarring after brain injury." Annals of the New York Academy of Sciences. 1048(1): 296-310. ]
Antisense GFAP retrovirus
An antisense GFAP retrivirus (PLBskG) has been implemented in suppressing growth and arresting astrocytes in the G1 phase of the cell cycle. This was due to the
downregulationof GFAP mRNA. However, a main caveat to the clinical application of this administration scheme is that the effects of PLBskG have been observed in normal and injured astrocytes. "In vivo" test are still required to observe the systemic affects of PLBskG. Huang QL, Cai WQ, Zhang KC. (2000). "Effect of the control proliferation of astrocyte on the formation of glial scars by antisense GFAP retrovirus." Chinese Science Bulletin, 45(1): 38-44.]
Recombinant monoclonal antibody to transforming growth factor-β2
As noted in the above section, transforming growth factor-β2 (TGFβ2) is an important glial scar stimulant that directly affects astrocyte proliferation. Exploiting this knowledge has allowed Logan "et al." to develop monoclonal antibodies to TGFβ2. Cerebral wounds were generated in rat brain models, and the antibodies were administered via the ventricles daily for 10 days. Subsequent analysis showed a marked reduction in all
Central Nervous Systemscarring. Particularly, extracellular matrix protein deposition ( laminin, fibronectin, and condroitin sulfate proteoglycans) was more similar to normal amounts (relative to the increased values in glial scars). Further, a reduction in glial scar cells (such as astrocytes and microglia), as well as a reduction in inflammation and angiogenesis, was observed. Logan A, "et al." (1999). Inhibition of glial scarring in the injured rat brain by a recombinant human monoclonal antibody to transforming growth factor-β2." European Journal of Neuroscience, 11: 2367-2374.]
Recombinant monoclonal antibody to interleukin-6 Receptor
Interleukin-6 (IL-6) is an important cytokine involved in glial scar formation; it has been observed to stimulate neuronal stem cell differentiation into astrocytes, thereby increasing the amount of reactive astrocytes during glial scar formation. A monoclonal antibody, MR16-1, has been used to target and block the IL-6 receptors in rat spinal cord injury models. In a study by Okada "et al.", mice were intraperitoneally injected with a single dose of MR16-1 immediately after generating a spinal cord injury. It was determine that the blockade of IL-6 receptors decreased the amount of astrocytes present at the spinal cord lesion. Further, the glial scar formation was decreased, presumably due to decreased amounts of astrocytes. Okada S, "et al." (2004). "Blockade of Interleukin-6 Receptor Suppresses Reactive Astrogliosis and Ameliorates Functional Recovery in Experimental Spinal Cord Injury." Journal of Neuroscience Research, 76: 265-276.]
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