Abstract
Somatic stem cell populations display a remarkable capacity to self-renew and generate specialised cell types throughout the life of the organism. In my thesis I examined extrinsic and intrinsic factors that regulate stem cell quiescence, a reversible state of growth arrest crucial to the preservation of somatic stem cell number and function in many systems. Skeletal muscle-specific stem cells, known as satellite cells (SCs) are responsible for skeletal muscle regeneration. The ability of skeletal muscle to regenerate declines with age. I identify fibroblast growth factor 2 (FGF2) as a potent mitogenic factor that is up-regulated in the aged muscle fibre and causes a loss of SC quiescence and depletion of the stem cell pool. Deletion of a negative regulator of FGF signalling, Sprouty1 (Spry1), in SCs increases stem cell loss, whereas over-expression of Spry1 partly prevents depletion. These experiments show that an age-associated change in the SC niche is partly responsible for stem cell depletion during ageing.In the adult forebrain, new neurons produced from neural stem cells (NSCs) in the hippocampus play an important role in learning and memory formation. I show that deletion of the chromatin remodelling enzyme chromodomain helicase DNA-binding protein 7 (CHD7) in NSCs results in a severe reduction in neurogenesis. I identify CHD7 as an essential regulator of NSC quiescence and self-renewal. Collectively, my results suggest that the regulation of the intrinsic chromatin landscape and the extrinsic niche environment are essential for somatic stem cell function, and may contribute to ageing when disrupted.
| Date of Award | 2014 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Albert Basson (Supervisor) |