Bain, OW; (2015) In vitro enhancement of retention and vascular support capacity of bone marrow derived stem cells for cardiac repair. Doctoral thesis , UCL (University College London).

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Abstract

Cardiovascular disease is a worldwide problem as the number one cause of death and disease. Although improvements in pharmaceutical and surgical interventions have increased patient survival post infarction, approximately half those that recover have a progress to congestive heart failure. Stem cell therapy is a strategy to improve functional recovery after myocardial injury. Many early phase clinical trials have been conducted throughout the world, albeit with variable results. It is postulated that the transplanted cells are not retained within the peri-infarct region and either apoptose or migrate to the spleen. This thesis aims to understand the functional characteristics of bone marrow mononuclear cells (BM-MNC) and Mesenchymal Stem Cells to characterise their adhesion and migration responses that are essential for successful cell retention. In vitro model assays were developed to mimic the physiological environment of the peri-infarct region using hypoxic conditions and fibronectin, an extracellular matrix that is highly upregulated in the infarct region. In vivo rat studies have shown Stromal Derived Factor-1 (SDF-1) stimulated MSCs improved cardiac function post infarction. In this study SDF-1 stimulation had no effect on the in-vitro adhesion and chemotaxis of MSCs and BM-MNCs. Both cell types had significantly decreased adhesion to fibronectin in hypoxic conditions To investigate the importance of Neuropilin-1 (NRP1) MSCs were knockdown for the protein. NRP1 knocked down MSCs had significantly decreased adhesion to fibronectin, chemotaxis to PDGF-AA, and interactions with endothelial cells. Expression of NRP1 was enhanced by basic fibroblast growth factor that enhanced adhesion in hypoxic conditions and increased vascular endothelial growth factor release.

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