Exploring the methylome and transcriptome of young adult and aged OPCs

Change log
Baror, Roey 

Remyelination is the restoration of myelin sheaths to denuded axons following demyelinating events, which occurs spontaneously in adult mammals, including humans. The principal cells which participate in remyelination are the Oligodendrocyte Progenitor Cells (OPCs). Similar to other regenerative processes, remyelination efficiency declines with ageing. It is still unknown how much of this decline can be attributed to intrinsic changes in the OPCs themselves rather than environmental changes arising from changes in the cellular niche. Thus, we currently have a fundamental gap in our knowledge regarding the basic biology of adult OPCs, and therefore the changes that occur to them with ageing. In order to address these questions, I have developed a method to reliably isolate all cell types of the oligodendrocyte (OL) lineage from adult rats. This allowed me to identify the specific transcriptome state unique to adult OPCs, which is different to the transcriptome of neonatal OPCs, upon which previous studies have focused. This included genes which support the notion that following the initial phases of developmental myelination, adult OPCs enter a quiescent mode, in a manner similar to other tissue resident stem cells. Moreover, using a recently established isolation method, I was able to isolate aged OPCs, and develop a transcriptional database that can allow researchers to explore the changes in aged OPCs and identify new targets for enhancing their function. Lastly, I present in this thesis novel ideas regarding the influence of microglia cell surface molecules on OPC differentiation. I show that changes in the cell surface of aged microglia are inhibitory for OPC differentiation into OLs, and that these changes in microglia are a result of the increase in TGFb levels with ageing. In summary, this dissertation introduces new tools and methods that will allow x further in-depth study of adult OPCs, and specifically will help to shed light on the role of adult OPCs in the CNS in homeostasis. Furthermore, I explore the changes that occur within OPCs as they age, and show how such changes reduce aged OPCs ability to efficiently facilitate the process of remyelination.

Franklin, Robin JM
Oligodendrocyte, stem cells, Ageing
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Cambridge Overseas Trust funding, AJA-Karten Trust, Cambridge Philosophical Society and Churchill College.