Cell therapy for the repair of the mammalian heart

Abstract

There are immense interests in utilising cell therapy for myocardial repair. Although bone marrow cells are the most extensively studied cell type to-date, evidences of the benefits of using these cells are conflicting. In this thesis, I explore the methodologies used for in-vitro and in-vivo studies of cell therapy, and define the potential of bone marrow cells for myocardial repair. I have identified a potential drawback with the use of green fluorescent protein for the cell therapy studies. The use of cardiac explants was also not suitable for my in-vitro studies of cell therapy. I further demonstrated that there were limitations in the current microscopic techniques used for identifying myocyte nucleus, and this can be a potential source of error in in-vivo studies in which myocyte nuclear events, such as proliferation, and transdifferentiation are evaluated. With this in mind, lineage tracing was used to show that bone marrow cells did not differentiate into myocytes when transplanted immediately after acute myocardial infarction. In addition, no functional improvement was also observed on echocardiography. To compliment my pre-clinical work, two randomised trials were conducted. The first trial showed that intramuscular or intracoronary injections of bone marrow cells into scarred myocardium did not contribute to any meaningful regeneration. The second trial investigated the potential cardioprotective paracrine effects of bone marrow cells, and showed that they did not provide additional cardioprotection when used as an adjunct during cardiopulmonary bypass. While these studies contributed to our understanding and planning of future work in this field, many key questions remain unanswered – whether bone marrow cells can truly benefit the heart, and if so, what are the mechanisms? When and to whom it should be given? Hopefully, my final study on novel biomarkers will eventually aid the identification of patients who will benefit from cell therapy