Is-14: Definition and Embryonic Origins of MSClike Stem Cells in The Adult Mammalian Heart

Harvey RP *, Chong JJH , Chandrakanthan V1 , Xaymardan M , Asli NS , Rashidianfar S , Prall OWJ ,


Objective: Identification of multi-potent stem cells in the adult mammalian heart has promoted a revision of the dogma that the heart is a post-mitotic organ with limited regenerative reserve, and stimulated clinical trials of stem cell therapies in patients with ischaemic cardiac disease, the most significant cause of death in developed countries. Our aim is to develop a quantitative framework for characterising mesenchymal stem cell (MSC)-like stem cells in the adult mouse heart, and to explore their role in homeostasis and potential for augmented regeneration. Materials and Methods: A colony-forming assay (colony-forming units-fibroblast; CFU-F) was used to define cardiac MSC-like cells in normal and genetically modified mice. Formal lineage tracing of cardiac CFUFs was performed using bone marrow transplantation and Cre recombinase genetic technology. Results: Cardiac CFU-Fs show long-term growth and are multi-potent for a variety of mesodermal and transgerm layer cell lineages in vitro and in vivo, and have a gene expression and cell surface receptor profile resembling bone marrow (BM) MSCs. However, adult cardiac CFU-Fs do not arise from the bone marrow in health or disease. They have their lineage origins in an embryonic stem cell population termed the proepicardium, which is derived from the heart progenitor fields and forms the coronary circulation and other interstitial cells of the heart. BM, heart and aortic CFU-F arise from different post-gastrulation cell lineage compartments. Cardiac CFU-F can be stimulated by growth factor treatments that improve heart repair after myocardial infarction. Conclusion: Our findings establish cardiac CFU-Fs as a stem cell population endogenous to the heart and likely dedicated to replacement of vascular, stromal and other cell types in homeostasis and repair. We propose that organ-specific CFU-Fs arise from the mesoderm and neural crest cells in organ-specific vascular beds, and understanding their organ-specific roles will open up new possibilities for regenerative therapies.