Medicine (RMH) - Theses
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ItemCharacterization of primary and transfected placental mesenchymal stem cell migration( 2014)Mesenchymal stem cells (MSCs) have enormous potential for their use in regenerative medicine. Bone marrow MSCs have been successfully used in clinical applications for decades. However, the large numbers of MSCs needed for prospective cellular therapies requires a plentiful, non-invasive and non-controversial source. One such source of MSCs is the human term placenta. Placental MSCs can be isolated in large numbers from different parts of the human term placenta and are being tested for their potential clinical benefit in the repair of damaged tissue. However, animal models show that MSCs do not migrate and engraft efficiently into the microenvironment of the injury site. This reflects our lack of knowledge of the important factors that promote MSC migration and engraftment. The general aim of this work was to investigate placental MSC migration. The specific aim was to identify the factor(s) that promote placental MSC migration, particularly those that stimulate placental MSC migration across the endothelial barrier, using in vitro and ex vivo models. The long-term goal was to increase the therapeutic potential of placental MSCs. This investigation was conducted on chorionic MSCs (CMSCs), which were isolated from the chorionic plate of the placenta. The CMSC29 cell line, created from CMSCs by transformation, was also used during this investigation for optimization and screening purposes. Both CMSCs and CMSC29 cells were characterised and met the accepted criteria for MSCs. Various quantitative methods were employed to investigate how the migration of CMSCs and CMSC29 cells was altered in response to different cues. A series of biological (SDF-1α, IL-6, HGF and endothelial activation), pharmacological (valproic acid) and environmental (oxygen concentration) factors were tested to examine their effect on CMSC migration. Of these factors, only valproic acid was shown to stimulate CMSC migration. Trans-endothelial migration assay was used to show that CMSCs migrate across the vascular endothelial barrier. However, none of the factors tested, which have been shown to stimulate bone marrow MSC migration in published studies, were able to induce CMSC migration. Finally, a pilot study described a novel placental vessel ex vivo perfusion model to study MSC migration. In summary, placental MSCs are able to migrate, but did not respond to stimuli of MSC migration in the same manner as has been reported for bone marrow MSCs. They did however respond to valproic acid as a stimulus. These data suggest that placental MSCs respond to different physiological cues, and employ different migration mechanisms to those of the widely studied bone marrow MSCs.