A study of astrocytes and endothelial cells in relation to scarring in multiple sclerosis

Astrocytes are the most numerous cell type in the brain. They support neurones maintain the microenvironment, are involved in neurotransmitter signalling and modulate neuronal-vascular communication. Throughout the vasculature a monolayer of endothelial cells (EC) lines the blood vessel lumen. In the brain, ECs and astrocytes collectively form a highly specialised blood brain barrier (BBB) which strictly regulates the passag~ of substances into the brain and is crucial for preservation of this unique milieu. Multiple sclerosis (MS) is a central nervous system (CNS) ~isease characterised by demyelinated lesions, inflammation, axonal loss and glial {', scarring. CNS injury induces gliosis· during which astrocytes become reactive, hypertrophic, and increase protein expression. Little is known about the mechanisms that induce these changes. In the early stages of MS spontaneous repair takes place, but with disease progression, repair is less frequent and lesions are filled with a glial scar composed of post-reactive astrocytes. The EC response to injury is to become activated and form new blood vessels from pre-existing ones (angiogenesis) to restore vascular supply. In MS, focal injury is likely to' elicit this response, disturb astrocyte-endothelial interaction as well as disrupt (BBB) integrity. Activated ECs secrete factors that have ' paracrine and autocrine effects. -As astrocytes are closely associated with ECs these factors might affect the astrocytes phen0!Xpe. Due to the chronic nature of MS, erratic and recurrent EC activation could influence scar deposition. The present study characterised astrocytes in chronic MS lesions and found that they have a characteristic scar phenotype, which is different from normal or reactive astrocytes. An examination of blood vessel density and EC activation in MS was performed, showing that vascular changes take place in MS, and suggesting that angiogenesis occurs during the disease process. Two in vitro studies have been undertaken and have resulted in the development of a model of quiescent astrocytes, and a cell culture system in which ECs can be grown in qUiescent and activated conditions. These models were used to investigate the effects of ECs on the astrocyte phenotype and to identify factors that potentially influence scar deposition.EThOS - Electronic Theses Online ServiceGBUnited Kingdo