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The mystery of brain repair: How do glial scars help or hinder central nervous system healing?
Glial scar formation (glial scarring) is a reactive cellular process involving astrocyte proliferation that occurs following injury to the central nervous system. Similar to scars in other organs and tissues, glial scars are the body's mechanism for protection and initiating the healing process. In the context of neurodegenerative diseases, glial scar formation has been shown to have both beneficial and detrimental effects. In particular, many molecules that inhibit neurodevelopment are secreted by cells within scars and these molecules can prevent full physiological and functional recovery of the central nervous system after injury or disease.
The main function of glial scar is to restore the physical and chemical integrity of the central nervous system.
Components of glial scar
Reactive astrocytes
Reactive astrocytes are the main cellular components of glial scars. Following injury, astrocytes undergo morphological changes, extend their processes and increase the synthesis of glial fibrillary acidic protein (GFAP). GFAP is an important intermediate filament protein that enables astrocytes to begin synthesizing more cytoskeletal support structures and extending pseudopodia. Ultimately, astrocytes form a dense mesh of cell membrane extensions that fill the gaps created by dying or declining nerve cells (called astrogliosis).
Microglia
Microglia are the second most important cell type within the glial scar. They are cells in the nervous system similar to the immune system's macrophages. Microglia are rapidly activated near the injury and secrete a variety of cytokines, active lipids, coagulation factors, reactive oxygen intermediates, and nerve growth factors.
Endothelial cells and fibroblasts
Multiple bioactive molecules secreted by microglia stimulate and recruit endothelial cells and fibroblasts, which help stimulate angiogenesis and collagen secretion in the injured area.
Glial scars prevent nerve regeneration and inhibit the growth of neurons.
Beneficial effects of glial scar
The ultimate function of the glial scar is to restore the physical and chemical integrity of the central nervous system. This is achieved by creating a barrier in the injured area that seals the boundary between neural and non-neural tissue and allows for the regeneration of a selective barrier to prevent the spread of further microbial infection and cellular damage.
Harmful effects of glial scar
However, glial scars also prevent neurons from regenerating. After injury to the central nervous system, axons begin to sprout and attempt to cross the injury site to repair the damaged area, but glial scars prevent the extension of these axons by physical and chemical means.
Major scar-inducing molecules
Transforming Growth Factor-β
Two subclasses of the transforming growth factor β family that are important for neurons are TGFβ-1 and TGFβ-2, which directly stimulate the activity of astrocytes, endothelial cells, and macrophages.
Interleukin
Interleukin-1 is a protein produced by mononuclear phagocytes that helps initiate an inflammatory response in astrocytes, leading to reactive astrogliosis and glial scar formation.
Techniques to inhibit glial scar formation
Olomosin
Olomoucine is a purine derivative that inhibits the function of cyclin-dependent kinases, thereby reducing the formation of glial scars.Inhibition of phosphodiesterase 4
Inhibition of phosphodiesterase 4 increases cyclic AMP levels in neurons, which has been shown to promote axonal growth.
Treatment or removal of glial scars
Glycosphingosylase ABC has been shown to degrade glial scars and promote recovery from spinal cord injury, especially when combined with other techniques such as nerve-guiding catheters, Schwann cell transplantation, and peripheral nerve autografts.
Although glial scars can play a certain protective role after nervous system injury, their ability to hinder nerve regeneration is worrisome. Faced with this duality, how should future research balance the protection and regeneration of glial scars?