Characterisation and Mechanism of Bone Marrow Cell-Induced Myocardial Protection

It is controversial whether the administration of bone marrow cells (BMCs) can repair the heart after an ischaemic insult and whether the mechanism of the putative beneficial effect is due to a paracrine action. By using an experimental model of simulated ischaemia of the atrial myocardium, I set up this thesis to understand the protective properties of BMCs on the human myocardium with different clinical conditions and to investigate the underlying mechanism. The results provide clear data that myocardial protection of BMCs is dose-dependent with a maximal protection, comparable to that of ischemic preconditioning, at a dose of ~1.5x106 cells/mg wet myocardium and that the similar effect can be achieved when BMCs were present before, during or after ischaemia. Allogeneic BMCs are as protective as the autologous cells and their capacity is unaffected by frozen storage or culture, but lost by magnetic isolation. In addition, the conditioned media, obtained after 30min of incubation of BMCs, can induce a protection similar to that of BMCs, an effect that is abolished by selective blockade of the insulin-like growth factor-1 receptor. Furthermore, disease states such as diabetes and poor left ventricular function or the long-term administration of the mitochondrial KATP channel opener nicorandil prevents the protective effect of BMCs, a consequence that appears to be due to an alteration in the myocardium for diabetes and nicorandil and mainly due to a defect in BMCs and also to a less responsive myocardium in heart failure. A final clinical study aimed to elucidate the effect of BMCs during cardiac surgery showed that BMCs have no additive protection to conventional cardioplegia during coronary artery bypass grafting. In this thesis I have characterised the cardioprotective potential of BMCs and identified some of the underlying mechanisms. The results are of clinical interest and they should generate novel hypotheses.