Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508625
Title: Muscular dystrophy cell therapy : an in utero approach using human fetal mesenchymal stem cells
Author: Wu, Pensée
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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Abstract:
Duchenne muscular dystrophy (DMD) is the most prevalent genetic neuromuscular disorder and affects 1 in 3,500 live male births. Lack of the protein dystrophin in muscle fibres causes permanent muscle damage, is lethal and despite various potential therapeutic strategies aimed at restoring dystrophin expression, has no cure. As DMD affects all skeletal muscles as well as the heart, a systemic treatment would be necessary and in utero stem cell transplantation is a promising way of achieving this. The identification of human fetal mesenchymal stem cells (hfMSC) in early gestation fetal blood offers the prospect of allogeneic or autologous cell therapy, while intrauterine administration would capitalise on ontological opportunities unique to the developing fetus. The aim of the study was to improve hfMSC engraftment and contribution to skeletal muscle fibres following intrauterine transplantation (IUT) in a mouse model of DMD. My project demonstrated that hfMSCs are easily isolated and expandable with the ability to undergo myogenesis in vitro. HfMSCs differentiated into mature myotubes following exposure to galectin-1 conditioned medium, while galectin-1 transduced hfMSCs showed significantly higher expression of myogenic markers compared to non-transduced hfMSCs. Co-culture experiments provided an in vitro model to explore the underlying mechanism for muscle differentiation of hfMSCs following IUT. HfMSCs were able to form chimeric myotubes by fusing with myoblasts isolated from E15 mouse embryos, evidence that they should be able to fuse with developing muscle fibres in vivo. Engraftment and differentiation into muscle fibres of hfMSCs injected intra-peritoneally into E15 mouse embryos in vivo was enhanced by using immunodeficient dystrophic host mice, postnatal muscle injury and additional neonatal hfMSC transplantation following IUT. In conclusion, my thesis supports the use of hfMSC as an attractive source for cell therapy and provides the background for further studies to optimise their engraftment and differentiation to underpin future clinical applications.
Supervisor: Fisk, Nicholas ; Morgan, Jennifer ; Dibb, Nick Sponsor: Wellbeing of Women ; Institute of Obstetrics and Gynaecology Trust
Qualification Name: Doctor of Medicine (Research) MD (Res) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.508625  DOI: Not available
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