A comparison of the molecular mechanisms involved in olfactory ensheathing cell and Schwann cell interactions with astrocytes

Fairless, Richard (2004) A comparison of the molecular mechanisms involved in olfactory ensheathing cell and Schwann cell interactions with astrocytes. PhD thesis, University of Glasgow.

Abstract

The transplantation of glial cells, including olfactory ensheathing cells (OECs) and Schwann cells, for the treatment of various CNS lesions, such as demyelination and spinal cord injuries, has attracted a lot of recent focus. However, there has been much debate as to which is the superior cell for these transplantation therapies. OECs are generally considered to be superior to Schwann cells due to their greater capacity for migration and their ability to co-exist within astrocyte-rich environments. In addition, OECs induce less reactivity in host astrocytes following transplantation. However, the mechanisms which determine the differential interactions of Schwann cells and OECs with astrocytes are at present unknown. The aim of this thesis was to determine the nature of these mechanisms, with intent to further characterise these very similar glial cell types, and to highlight possible molecular targets for improving the potential of OECs and Schwann cells for transplantation. I have addressed these issues by using in vitro cultures which model the interactions of OECs and Schwann cells with astrocytes, reflecting those which occur following transplantation. Initial studies confirmed that Schwann cells have a limited ability to migrate in the presence of astrocytes in comparison to OECs. However, using migration assays it was demonstrated that Schwann cells are not inferior to OECs with regard to their inherent migrational capacity, but that this inhibition only results upon contact with astrocytes. In agreement with this, Schwann cells displayed greater adhesion than OECs to astrocytes, reflecting their reduced migration upon this substrate. To identify factors which influence the different migrational capacities of OECs and Schwann cells following astrocyte contact, I have investigated the role of the cell adhesion molecule, N-cadherin. Previous studies demonstrated that the inhibition of Schwann cell migration upon astrocyte monolayers is N-cadherin dependent, suggesting that this could be a difference between OECs and Schwann cells. I have shown here that N-cadherin is present on both OECs and Schwann cells, and is functional with regard to cell-cell interactions. However, using both N-cadherin peptide inhibitors, and siRNA to reduce N-cadherin expression, it was also demonstrated that OECs and Schwann cells have a different dependency upon N-cadherin for cell-cell interactions. Schwann cells, but not OECs, were dependent upon N-cadherin to form strong adhesions. In addition, removal of N-cadherin overcame astrocyte-induced inhibition of migration in Schwann cells, and allowed them to intermingle with astrocytes in a manner more akin to OEC-astrocyte interactions. Thus, this demonstrates that not only do Schwann cells and OECs differ in their dependency upon N-cadherin for adhesion and migration, but also that N-cadherin is a major factor in determining the ability of Schwann cells to intermingle with astrocytes. In conclusion, both the function of N-cadherin and the presence of reactive astrocytes, are involved in determining the ability of Schwann cells and OECs to migrate within astrocyte rich areas. Schwann cells differ from OECs in that they are dependent upon N-cadherin function for both adhesion and migration following interactions with astrocytes. In addition, unlike OECs, Schwann cells secrete factors which induce astrocytosis. Therefore, N-cadherin, or its various signalling components, and the putative factors secreted by Schwann cells, may now offer themselves as potential targets for intervention in order to improve the migration and integration of the cellular transplant into the host. (Abstract shortened by ProQuest.).

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Sue Barnett
• Keywords: Neurosciences
• Date of Award: 2004
• Depositing User: Enlighten Team
• Unique ID: glathesis:2004-74195
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Sep 2019 15:33
• Last Modified: 23 Sep 2019 15:33
• URI: https://theses.gla.ac.uk/id/eprint/74195