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Title: Neural differentiation of human fetal mesenchymal stem cells
Author: Kennea, Nigel Leonard
ISNI:       0000 0001 3597 1315
Awarding Body: Imperial College London (University of London)
Current Institution: Imperial College London
Date of Award: 2007
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The potential of mesenchymal stem cells (MSC) to differentiate into neural lineages has raised the possibility of autologous cell transplantation as therapy for neurological diseases. There are, however, no studies reporting significant numbers of oligodendrocytes, the myelinforming cells of the central nervous system, derived from MSC. We have recently identified a population of circulating human fetal MSC that are highly proliferative and readily differentiate into bone, cartilage, fat and muscle. I demonstrated for the first time that primary fetal MSC differentiate into cells resemblifl neural precursors and then oligodendrocytes both in vitro and in vivo. By exposing cells to a neuronal conditioned medium, rates of oligodendrocyte differentiation approaching 50% were observed, and cells appeared to mature appropriately in culture. Importantly, the differentiation of a clonal population into both mesodermal (bone) and ectodermal (oligodendrocyte) lineages was achieved. In the developing murine brain, cells integrated but oligodendrocyte differentiation of naiVe fetal MSC was very low. The proportion of oligodendrocyte differentiation was increased (from 0.2% to 4%) by pre-exposing the cells to differentiation medium prior to transplantation. The process of in vivo differentiation occurred without cell fusion. Although the main focus of this thesis was oligodendrocyte differentiation, I also recapitulated controversial published work into neuronal differentiation of MSC. The exposure of cells to the reducing agent butylated hydroxyanisole induced rapid changes in cell morphology and expression of neuronal markers. These 'differentiated' cells did not, however, appear functional with no upregulation of voltage-gated sodium channels or synaptophysin. Finally, while stem cells offer promise for correction of brain diseases, one major obstacle is the poor survival of grafted cells. Investigation of apoptotic signalling showed fetal MSC have functional apoptotic machinery in both the intrinsic (mitochondrial) and extrinsic (death receptor) pathways which could be manipulated to prolong stem cell survival by inhibition of death signalling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available