Chondroitin sulphate proteoglycans: inhibitory components of the glial scar

Epidemiology studies of traumatic brain injury (TBI) show individuals with a prior history of TBI experience an increased risk of future TBI with a significantly more detrimental outcome. But the mechanisms through which prior head injuries may affect risks of injury during future head insults have not been identified. In this work, we show that prior brain tissue injury in the form of mechanically induced axonal injury and glial scar formation can facilitate future mechanically induced tissue injury. To achieve this, we use finite element computational models of brain tissue and a history-dependent pathophysiology-based mechanically-induced axonal injury threshold to determine the evolution of axonal injury and scar tissue formation and their effects on future brain tissue stretching. We find that due to the reduced stiffness of injured tissue and glial scars, the existence of prior injury can increase the risk of future injury in the vicinity of prior injury during future brain tissue stretching. The softer brain scar tissue is shown to increase the strain and strain rate in its vicinity by as much as 40% in its vicinity during dynamic stretching that reduces the global strain required to induce injury by 20% when deformed at 15 s⁻¹ strain rate. The results of this work highlight the need to account for patient history when determining the risk of brain injury.

Neural cell death is the main feature of all retinal degenerative disorders that lead to blindness. Despite therapeutic advances, progression of retinal disease cannot always be prevented, and once neuronal cell damage occurs, visual loss cannot be reversed. Recent research in the stem cell field, and the identification of Müller glia with stem cell characteristics in the human eye, have provided hope for the use of these cells in retinal therapies to restore vision. Müller glial cells, which are the major structural cells of the retina, play a very important role in retinal homeostasis during health and disease. They are responsible for the spontaneous retinal regeneration observed in zebrafish and lower vertebrates during early postnatal life, and despite the presence of Müller glia with stem cell characteristics in the adult mammalian retina, there is no evidence that they promote regeneration in humans. Like many other stem cells and neurons derived from pluripotent stem cells, Müller glia with stem cell potential do not differentiate into retinal neurons or integrate into the retina when transplanted into the vitreous of experimental animals with retinal degeneration. However, despite their lack of integration, grafted Müller glia have been shown to induce partial restoration of visual function in spontaneous or induced experimental models of photoreceptor or retinal ganglion cell damage. This improvement in visual function observed after Müller cell transplantation has been ascribed to the release of neuroprotective factors that promote the repair and survival of damaged neurons. Due to the development and availability of pluripotent stem cell lines for therapeutic uses, derivation of Müller cells from retinal organoids formed by iPSC and ESC has provided more realistic prospects for the application of these cells to retinal therapies. Several opportunities for research in the regenerative field have also been unlocked in recent years due to a better understanding of the genomic and proteomic profiles of the developing and regenerating retina in zebrafish, providing the basis for further studies of the human retina. In addition, the increased interest on the nature and function of cellular organelle release and the characterization of molecular components of exosomes released by Müller glia, may help us to design new approaches that could be applied to the development of more effective treatments for retinal degenerative diseases.

Glial cells and extracellular matrix (ECM) molecules are crucial for the maintenance of brain homeostasis. Especially because of their actions regarding neurotransmitter and ionic control, and synaptic function, these cells can potentially contribute to the hyperexcitability seen in the epileptogenic, while ECM changes are linked to synaptic reorganization. The present review will explore glial and ECM homeostatic roles and their potential contribution to tissue plasticity. Finally, we will address how glial, and ECM changes in the epileptogenic zone can be seen in magnetic resonance imaging (MRI), pointing out their importance as markers for the extension of the epileptogenic area.

This article is part of the Special Issue "NEWroscience 2018".

Peripheral nerve injury is a frequent clinical problem and causes loss of motor and sensory functions for patients. Though some inherent regeneration capacity exists, this is often very limited in the cases of nerve tissue gaps. The design of a nerve conduit that results in successful nerve axon regeneration across these gaps and recovery of normal functions is a significant challenge for researchers in the fields of tissue engineering and regenerative medicine. This chapter includes a historic background to this research area and summarizes the current knowledge of various biomaterials, fabrication techniques and structural modifications, and the inclusion of cell and molecular therapies used in the production of nerve conduits.

Many studies, using pre-clinical models of SCI, have demonstrated the efficacy of chondroitinase ABC as a treatment for spinal cord injury and this has been confirmed in laboratories worldwide and in several animal models. The aim of this review is report the current state of research in the field and to compare the relative efficacies of these new interventions to improve outcomes in both acute and chronic models of SCI. We also report new methods of chondroitinase delivery and the outcomes of two clinical trials using the enzyme to treat spinal cord injury in dogs and disc herniation in human patients. Recent studies have assessed the outcomes of combining chondroitinase with other strategies known to promote recovery following spinal cord injury and new approaches. Evidence is emerging that one of the most powerful combinations is that of chondroitinase with cell transplants. The particular benefits of each of the different cell types used for these transplant experiments are discussed. Combining chondroitinase with rehabilitation also improves outcomes. Gene therapy is an efficient method of enzyme delivery to the injured spinal cord and circumvents the issue of the enzyme’s thermo-instability. Other methods of delivery, such as via nanoparticles or synthetic scaffolds, have shown promise; however, the outcomes from these experiments suggest that these methods of delivery require further optimization to achieve similar levels of efficacy to that obtained by a gene therapy approach. Pre-clinical models have also shown chondroitinase is efficacious in the treatment of other conditions, such as peripheral nerve injury, stroke, coronary reperfusion, Parkinson’s disease and certain types of cancer. The wide range of conditions where the benefits of chondroitinase treatment have been demonstrated reflects the complex roles that chondroitin sulphate proteoglycans (its substrate) play in health and disease and warrants the enzyme’s further development as a therapy.

Chondroitinase ABC I (cABC I) can degrade inhibitory molecules for axon regrowth at the site of damage after spinal cord injury (SCI). One of the main problems in the practical application is the possibility of structural changes that lead to the inactivation of the enzyme. In current work, three variants of cABC I was designed and constructed by manipulation of a short helix conformation (Gln⁶⁷⁸-Leu⁶⁷⁹-Ser⁶⁸⁰-Gln⁶⁸¹); where Gln residues were converted to Glu. According to the enzyme kinetics studies, the catalytic efficiency of the Q681E and double mutant (Q678E/Q681E) increases in comparison with WT enzyme; while that of Q678E decreases. It was also shown that the rate of the inactivation of the enzyme variants over time is greater in WT and Q678E variants than that of the Q681E and double mutant. Negative values of entropy change of thermal inactivation measurements; demonstrate that inactivation of the WT and Q678E variants are mainly originated from aggregation. These observations can be explained by considering the repulsive electrostatic interaction between enzyme molecules that prevents protein aggregation over time. It is concluded that increasing the solubility of the Q681E and double mutant via favorable interactions of surface-exposed charged residues with dipole momentum of water molecules accompanied by the presence of intermolecular repulsive electrostatic interaction leads to decreasing the rate of aggregation in both long-term storage and heat-induced structural changes.