Fibronectin aggregation in rat astrocytes a role of integrins? In pursuit of enhancing remyelination in multiple sclerosis.

Versluijs, J. (Joris) (2013) Fibronectin aggregation in rat astrocytes a role of integrins? In pursuit of enhancing remyelination in multiple sclerosis. thesis, Medicine.

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Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, causing neurological disabilities in young adults. Remyelination is the process in which lost myelin sheaths are restored along demyelinated axons. This is necessary to restore saltatory conduction and, more importantly, to prevent axonal loss. Remyelination does occur is MS, but ultimately fails as the disease progresses. The failure of remyelination is likely mediated by many factors, including the extracellular signalling environment. Expression of the extracellular matrix protein fibronectin (Fn) is transiently increased in areas of demyelination and its expression declines as remyelination proceeds. In chronically demyelinated lesions, where remyelination fails, Fn expression persists in the form of aggregates. These aggregates are most likely formed in the process of astrogliosis. Fn aggregates impair remyelination in animal models and may also contribute to remyelination failure in MS. In vitro, stimulation of astrocytes with the TLR3 agonist Poly I:C or with the TLR4 agonist LPS induces Fn aggregation. In this study we focused on astrocyte mediated Fn aggregation upon stimulation with Poly I:C and the role of integrins in this process. Using integrin-blocking antibodies, we demonstrated that astrocyte adhesion to Fn was mediated by β1 and αVβ5, but not by β3. Stimulation of the astrocytes with Poly I:C did not influence their adhesion to Fn. The role of β1 and αVβ5 integrins in Fn adhesion might indicate their involvement in Fn aggregation. To address this hypothesis, the effect of integrin-blocking on Fn aggregation was assessed. Immunocytochemistry showed an increase in fibrillar Fn on the cell surface of Poly I:C stimulated astrocytes, which might indicate increased Fn aggregation. Blocking the RGD binding site, a renowned protein-recognition site present in fibronectin, did reduce fibrillar Fn expression, but did not abolish it, indicating that astrocytes are capable to form Fn fibrils in an RGD-independent manner. Furthermore, we show that stimulation of astrocytes with Poly I:C reduces their αVβ5 cell surface expression. Concluding, we show that stimulation of astrocytes with Poly I:C decreases αVβ5 cell surface expression, which might induces Fn fibril formation. Analysing the process of astrocyte mediated Fn aggregation and identifying which integrins are involved is crucial to develop means to disturb Fn aggregate deposition and facilitate Fn clearance in order to enhance remyelination in MS lesions.

Item Type:	Thesis (Thesis)
Supervisor name:	Baron, dr. Wia and Sikkema, dr. Erik
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:56
Last Modified:	25 Jun 2020 10:56
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/1681

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