Molecular interventions to overcome the ageing of CNS stem cells

Oligodendrocyte progenitor cells (OPCs) are the dominant tissue-specific stem cell of the central nervous system (CNS). In the adult, OPCs primarily differentiate into oligodendrocytes, the cell type that wraps neurons with myelin allowing for efficient signal transduction down the axon. Increasingly, the process of adult myelination is understood as a key process in learning, memory formation, and promoting overall CNS health. With ageing, the capacity for OPCs to both self- renew and differentiate into myelinating oligodendrocytes is impaired. This loss of function is particularly detrimental for patients with demyelinating diseases such as Multiple Sclerosis. The failure of OPCs to differentiate into oligodendrocytes contributes to the progressive worsening of the symptoms with ageing. As such, there is a therapeutic imperative to better understand the ageing process of OPCs in order to find possible interventions that will overcome their age-related dysfunction. Recent advances in the generation of induced pluripotent stem cells provide proof that all cells, regardless of age, can be reconverted into embryonic pluripotent stem cells, thereby shedding all the hallmarks of the ageing process. This work provides evidence that the ageing process on a cellular level is not immutable; rather, all cells can be rejuvenated. In each of the results chapters included in this thesis, I ask and then address four outstanding questions in the field of OPC ageing biology: 1. What governs the activity-state of adult OPCs? 2. Do OPCs irreversibly lose their plasticity during physiological ageing? 3. What causes this loss of activity in aged OPCs? 4. Are there molecular interventions that might overcome the age phenotype of aged OPCs? Addressing these questions in my thesis, I identify a vascular niche for OPCs in the adult animal and find that Wnt signaling underlies the activity-state of the quiescent adult OPC. I identify that overexpression of the reprogramming factor Myc can, alone, coax an aged quiescent OPC to behave more like a neonatal one. I describe how age-related changes in niche matrix mechanics drive the ageing-phenotype of OPCs, and how OPCs sense and respond to these changes with the mechano-transduction protein Piezo1. Finally, I have developed a novel, systemically delivered, cell-type-specific, genome engineering technique to perturb age-related genes in adult rodents. The work presented in this thesis provides a new understanding of OPCs in homeostasis and in ageing. By identifying multiple interconnecting signalling-pathways by which adult and aged OPCs can re-activate, I have identified multiple points of therapeutic intervention. Finally, this systemically-administered but cell-type specific genome-engineering technology could be used to construct one-generation transgenic animals in an adult rodent and could have therapeutic implications for a broad-spectrum of human diseases.Harvard-Cambridge Herchel Smith Postgraduate Scholarshi