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Mohan, Hema (2010): Extracellular matrix and oligodendrocyte regulators in different types of multiple sclerosis lesions: Implications for lesion development and regulation of remyelination. Dissertation, LMU München: Faculty of Biology
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Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) accompanied by demyelination and axonal loss. Only a minority of the demyelinated MS lesions gets remyelinated. In animal models, however, remyelination is the default program following immune-mediated or toxic demyelination. This thesis aims to find factors regulating remyelination in MS. The starting point was autoptic tissue from MS patients. First, different types of MS lesions were macrodissected namely, chronic inactive demyelinated lesions that had failed to remyelinate, lesions undergoing active demyelination and remyelinated lesions. Healthy white matter was used as control tissue. Gene expression profiles of these lesions were established using quantitative PCR low density arrays. Thereby the focus was on the extracellular matrix (ECM) and on factors known to regulate the biology of oligodendrocytes. ECM components can regulate oligodendrocyte differentiation and modify immune reactions in multiple ways, e.g., by sequestering or displaying growth factors and by directly interacting with immune cells and glial cells. The expression of 50 ECM components and 34 ECM degrading enzymes was measured by qPCR. COL1A1, COL3A1, COL5A1 and COL5A2 chains were strongly induced in active lesions and even more in chronic inactive lesions. These collagen polypeptide chains interact to form collagen types I, III and V, which are grouped as fibrillar collagens. Furthermore, two Small Leucine Rich Proteoglycans (SLRPs), biglycan and decorin, which can decorate fibrillar collagens, were also strongly induced. Immunostaining localized the fibrillar collagens, biglycan, and decorin around blood vessels. These ECM molecules were largely seen in the perivascular space closely associated with infiltrating immune cells forming a mesh between the endothelium and the astrocytic glia limitans. In active lesions collagen V was also seen in the heavily infiltrated brain parenchyma. Since these ECM molecules were found largely in the perivascular space close to immune cells and hardly in the surrounding parenchyma where oligodendrocyte differentiation takes place, the interaction of these ECM components with immune cells was further analysed. In vitro experiments revealed that the fibrillar collagens I and III inhibited the monocytic production of CCL2 (MCP-1), an inflammatory chemokine thought to be involved in the recruitment of immune cells to the inflamed brain. This suggests that the induced fibrillar collagens may contribute to the limitation of MS lesions expansion by inhibition of the CCL2 production by monocytes. The second set of analysed genes comprised 32 factors regulating survival, proliferation and/or differentiation of oligodendrocytes and 18 receptors of these genes. The key factors for oligodendrocyte differentiation (IGF1, IGF2 and CNTF) and oligodendrocyte proliferation (FGF2 and PDGFAA) were still present in demyelinated lesions, although their expression ratio was altered. The most striking result was the up-regulation of FGF9 in a subset of chronically demyelinated lesions, but in none of the remyelinated shadow plaques. The potential functional role of this observation was investigated by treating myelinating rat central nervous system cultures with exogenous FGF9. In this experimental setting, FGF9 inhibited the ability of mature oligodendrocytes to myelinate and ensheath axons. All these data suggests that the induction of FGF9 in some chronic MS lesions is one of the inhibitory mechanisms accounting for the failure of remyelination. Together, this thesis has two main findings: A) Fibrillar collagens, biglycan and decorin form a perivascular fibrosis and the fibrillar collagens I and III inhibit production of CCL2 by monocytes. Inhibition of CCL2 production by fibrillar collagens might contribute to lesion confinement. B) Expression profiles of remyelinated MS lesions were established for the first time and thereby, up-regulation of FGF9 in demyelinated, but not in remyelinated lesions was revealed. The inhibition of myelination in vitro by FGF9 suggests that this is one potential mechanism to explain why demyelinated lesions expressing higher FGF9 level fail to remyelinate.