The cardiovascular reparative properties of bone marrow mesenchymal precursor cells.

Despite seminal advances in its management, the burden of cardiomyopathy remains substantial, providing the stimulus for intense research into new therapeutic options, including the use of stem cells. Of the various adult-derived cell types that have been investigated, mesenchymal stromal/stem cells (MSC) are notable for their lack of immunogenicity and their capacity to mediate vascular and myocardial repair. While numerous studies have evaluated the use of plastic adherence-isolated, ex vivo expanded MSC for the treatment of ischaemic heart disease, little attention has been given to the use of MSC in the context of nonischaemic heart disease. The studies described in this thesis address the issue of optimising the efficacy of mesenchymal cell therapy, by using selective, antibody-based isolation of immature, mesenchymal precursor cells (MPC). Furthermore, they evaluate the reparative benefits of immunoselected MPC in a newly described, preclinical model of nonischaemic cardiomyopathy (NICM), using NOGA® XP navigation technology to perform targeted, intramyocardial cell delivery. In cell-based experiments, human bone marrow MPC, prepared by prospective immunoselection using the STRO-1 monoclonal antibody, were compared to donor-matched, plastic adherence-isolated MSC (PA-MSC). The ex vivo cultured progeny of STRO-1-enriched cells were found to possess a more immature and “stem-like” phenotype than conventional PA-MSC, also displaying greater expression of cardiovascular-relevant cytokines and stronger cardiovascular paracrine activity. Similar benefits were observed for human MPC that were isolated by using an alternative antibody, STRO-3. Unlike STRO-1, this marker was not human-species specific, enabling its use for selective preparation of ovine bone marrow MPC, as well. Preclinical NICM was reproducibly induced in Merino sheep, by titrated dosing of the anthracycline drug, doxorubicin, via the coronary arteries. Using a combination of cardiac magnetic resonance imaging, echocardiography and histology, this large animal model was found to share many of the features of clinical NICM, including the increased presence of myocardial fibrosis. Electromechanical characterisation of this model, using the NOGA® XP Cardiac Navigation System, demonstrated for the first time, the system’s potential to identify myocardial segments with increased fibrosis in NICM. This information was used to facilitate intramyocardial transplantation of allogeneic, STRO-3-selected, ovine MPC in the anthracycline model of cardiomyopathy. Cell therapy was found to attenuate left ventricular remodelling and prevent the deterioration of cardiac function that was observed in placebo-treated animals. The MPC-induced benefits were accompanied by reduction of cardiac fibrosis and enhancement of cardiomyocyte proliferation and myocardial neovascularisation, which were most likely mediated by paracrine mechanisms. In summary, the studies described in this thesis provide new evidence confirming the merits of selective isolation of bone marrow MPC and demonstrate that the pleiotropic, reparative effects of these cells may extend their therapeutic utility to nonischaemic cardiac disease.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201