Glial scar
Glial scar | |
---|---|
H&E-LFB stain. | |
Specialty | Pathology |
Causes | Trauma |
A glial scar formation (
In the context of neurodegeneration, formation of the glial scar has been shown to have both beneficial and detrimental effects. Particularly, many neuro-developmental
Scar components
The glial scar is composed of several components briefly discussed below.
Reactive astrocytes
Reactive
Another important caveat of the astrocytic response to CNS injuries is its heterogeneity. Particularly, the response of the astrocytes to the injury varies depending on factors such as the nature of the injury and the microenvironment at the injury location.[7][8] Further, the reactive astrocytes in the immediate vicinity of the injury increase gene expression, thus compounding the response of other astrocytes and contributing to the heterogeneity. Particularly, astrocytes closest to the lesion generally secrete more inhibitory molecules into the extracellular matrix.[2]
Microglia
Endothelial cells and fibroblasts
The various biologically active molecules secreted by microglia stimulate and recruit
Basal membrane
The basal membrane is a
Beneficial effects of the scar
The ultimate function of the glial scar is to reestablish the physical and chemical integrity of the CNS. 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 revascularization of blood capillaries to increase the nutritional, trophic, and metabolic support of the nervous tissue.[2]
Detrimental effects of the scar
The glial scar also prevents neuronal regrowth. Following trauma to the CNS, axons begin to sprout and attempt to extend across the injury site in order to repair the damaged regions. However, the scar prevents axonal extensions via physical and chemical means. Astrocytes form a dense network of
Primary scar molecular inducers
The formation of the glial scar is a complex process. Several main classes of molecular mediators of gliosis have been identified and are briefly discussed below.
Transforming growth factor β
Two neuronally-important subclasses of transforming growth factor family 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.[11] Experimental reduction of TGFβ-1 and TGFβ-2 has been shown to partially reduce glial scarring.[12]
Interleukins
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.[13][14]
Cytokines
The cytokine family 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.[15] Further, FGF2 production increases after injury to the brain and spinal cord. FGF2 has also been shown to increase astrocyte proliferation in vitro.[16][17]
Ciliary neurotrophic factor
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
Upregulation of nestin intermediate filament protein
Suppression of glial scar formation
Several techniques have been devised to impede scar formation. Such techniques can be combined with other neuroregeneration techniques to help with functional recovery.
Olomoucine
Olomoucine, a purine derivative, is a
Recent work has also shown that olomoucine suppresses
Inhibition of phosphodiesterase 4 (PDE4)
Phosphodiesterase 4 is a member of the
Ribavirin
Ribavirin is 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 five days following brain trauma was shown to significantly decrease the number of reactive astrocytes.[24]
Antisense GFAP retrovirus
An antisense GFAP retrovirus (PLBskG) to reduce GFAP
Recombinant monoclonal antibody to transforming growth factor-β2
As noted in the above section,
Recombinant monoclonal antibody to interleukin-6 receptor
Interleukin-6 (IL-6) is thought to be a molecular mediator of glial scar formation. It has been shown to promote differentiation of neural stem cells into astrocytes.[citation needed] 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. Blockade of IL-6 receptors decreased the number of astrocytes present at the spinal cord lesion and this decrease was associated with a reduction in glial scarring.[27]
Glial scar treatment or removal
Chondroitinase ABC has been shown to degrade glial scars.
See also
References
- PMID 14999065.
- ^ S2CID 13652357.
- S2CID 16748373.
- ^ 14561854
- S2CID 205026020.
- PMID 14735117.
- ^ 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.
- ^ 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
- ^ 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." Experimental Neurology 144: 381-399.
- ^ Asher RA, et al. (2000). "Neurocan is upregulated in injured brain and in cytokine-treated astrocytes." Journal of Neurosciemce 20, 2427–2438.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Lander C, et al. (1997). "A family of activity-dependent neuronal cell-surface chondroitin sulfate proteoglycans 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Neumann, S., et al. (2002). "Regeneration of Sensory Axons within the Injured Spinal Cord Induced by Intraganglionic cAMP Elevation." Neuron 34, 885–893.
- ^ Nikulina, E. et al. (2004). "The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery", Proc Natl Acad Sci USA 101(23): 8786–8790.
- ^ Pekovic, S., et al. (2006). "Downregulation of glial scarring after brain injury", Annals of the New York Academy of Sciences 1048(1): 296-310.
- ^ 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.
- ^ 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.
- ^ 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.
- S2CID 4430737.
- ^ "Re-engineered enzyme could help reverse damage from spinal cord injury and stroke". August 24, 2020.
- S2CID 10605553.
- PMID 15689553.
- PMID 21753849.