Content:
Reports of stem cells within the postnatal mammalian heart, and perivascular stem cells in many other post-natal organs, have stimulated great interest in regenerative strategies to treat cardiovascular diseases. However, a remaining fundamental question is the biological origins of these stem cell populations.Here, an adapted form of the CFU-F assay, originally used to characterise Bone Marrow (BM) Mesenchymal Stem Cells (MSCs), is used to study the origin of cardiac CFU-F (cCFU-F): a novel population of cardiac perivascular MSC-like cells that possess in vitro stem cell properties. Combining this assay with murine genetically labelled BM transplantation, evidence is provided against adult BM as a major source for cCFU-F after physiological ageing and myocardial infarction (MI), with or without G-CSF cytokine mobilisation. Using genetic Cre-Lox lineage tracing models, the neural crest lineage (Wnt1-Cre) and de-differentiated cardiomyocytes (Myl2-Cre, Nkx2-5-IRES-Cre) are excluded as potential origins for cCFU-F. However, the embryonic epicardium (Gata5-Cre, WT1-CreERT2) is shown to be the major source of cCFU-F throughout ontogeny after physiological ageing and after MI. Furthermore, Aortic CFU-F are shown to be from mixed origins, partly from mesoderm (Mesp1-Cre) and partly from the neural crest, whilst BM CFU-F have a different lineage origin to both cardiac and aortic CFU-F. These results pave the way for development of future therapies using this novel stem cell population. Specifically, defining the epicardial origin of cCFU-F allows known mechanistic pathways employed by the epicardium during cardiogenesis to be exploited for possible regenerative strategies. Evidence that CFU-F lineage origins vary depending on the organ from which they are isolated is consistent with the mosaic origins of vascular progenitors. This has important implications for views on cardiovascular function and disease.
Note:
Dissertation University of New South Wales. Victor Chang Cardiac Research Institute 2010
Language:
English
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