Glial cells in health and disease

Abstract

Glial cells are often considered to be ‘supporting cast’ members in the nervous system, with ancillary roles in providing nutrient and structural support to neurons. However, glial cells have many essential roles, including the myelination of nerves to allow information to be transmitted rapidly and efficiently. My thesis has largely focused on the role of myelinating glial cells in health and disease. I first studied a population of malignant oligodendrocyte-like cells that form glial tumors in the central nervous system, called oligodendroglioma. For the rest of my thesis, I focused on Schwann cells in the peripheral nervous system. In Chapter 2 of my thesis, I describe my investigation into the role of extracellular vesicles in controlling oligodendroglioma growth by mediating heterotypic and homotypic cell-cell interactions. I revealed that oligodendroglioma tumor cells secrete extracellular vesicles that carry cytotoxic cargo to induce cell death in neighboring cells. Furthermore, I implicated a gene involved in extracellular vesicle biogenesis, SMPD3, in negatively regulating oligodendroglioma growth by controlling the synthesis of extracellular vesicles (Chapter 2). I then studied the development of Schwann cells, and their transition into repair Schwann cells post nerve injury. I characterized the dynamic expression patterns of a panel of transcriptional regulators during development and in repair Schwann cells post-injury (Chapter 3). I then used this panel of markers to ask whether the ets domain transcription factor Etv5, expressed transiently in Schwann cell precursors, played a role in regulating Schwann cell development and in repair Schwann cells by using a hypomorphic Etv5 mutant mouse model (Chapter 4). While Etv5 mutants had no apparent defects in Schwann cell development, I describe several important caveats and future considerations. Finally, I performed the first steps towards developing a non-integrative, triple transcription factor mediated lineage conversion strategy for the generation of induced repair Schwann cells from mouse embryonic fibroblasts (Chapter 5). In conclusion, I have gained new insights on how glial cells in a healthy and diseased state are regulated. My findings have therapeutic implications for the treatment of oligodendroglioma tumors in the central nervous system, and for peripheral nerve repair.