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Dr. Pieter Doevendans,
State of the art session on stem cells with attention for cardiac stem cells and the potential role of induced pluripotent stem cells (IPS) to generate cardiomyocytes.
The session was chaired by Gerd Hassenfuss and Pieter A. Doevendans.
Several issues were uncovered. Anke Smits (Oxford) introduced the concept of using cardiomyocyte progenitor cells (CMPCs) to generate cardiomyocytes and nicely showed that a mixture of CMPC with epicardium-derived stem cells (EPDCs) is even more effective in vivo for cardiac repair than each of the cell type separately.
Another key finding was the very early beneficial effect of stem cell therapy in the mouse model (within 2 days). EPDCs contribute to vessel formation and also become cardiomyocytes via endothelial to mesenchymal cell transition (EMT). Research is proceeding to detect factors that control EMT, in addition to TGF-b.From the same group Nicola Smart gave a lecture on the role of thymosin b4 on epicardial cells. She showed nice pictures of cells from the proepicardium that overgrow the looping heart to form the outer myocardial layer, followed by the formation of the epicardial vessels. She showed the strong response on stimulation of EPDCs post infarction with thymosin b4. Activation leads to increased numbers of vascular smooth muscle cells as well as cardiomyocytes. With beautiful labeling experiments it was shown that about 1% of the cells mature into cardiomyocytes. Although a very promising finding, 1% is not sufficient to explain the beneficial effects observed in vivo. Here also the search is ongoing to find molecules to stimulate endogenous repair.
Lior Gepstein reviewed many years of heart work with human embryonic stem (hES) cells and the potential value of culturing cardiomyocytes to perform transplantation. With optical mapping, he showed the importance of electrical coupling between the host tissue and injected cells. Cells from skeletal myoblasts do not couple and are therefore pro-arrhythimic, while hES derived cardiomyocytes form a syncytium even in the rat heart and reduce the inducibility of arrhythmias. Next he moved to more recent work with induced pluripotent stem cell derived cardiomyocytes, and showed that it is possible to make cardiomyocytes starting from T-cells. The cardiomyocytes were successfully injected in rat models. Here, further work needs to be done to increase the safety without losing the efficiency of the system.
The dilemma was further discussed in the final lecture by Daniel Sinnecker. He focused on the value of induced pluripotent stem cell technology to model cardiac disease. Nice studies were shown for a family with a HERG mutation (LQT2 type 2 syndrome). He showed the importance of genetic background as the phenotype only became apparent after creating isogenic lines where the mutation is the only variable. He also addressed the issues surrounding the reprogramming vectors and the potentially hazardous effects of tumorigenesis and teratoma formation. On differentiation in vivo, there is wide heterogeneity in the resulting cellular phenotype. On differentiation in vitro, maturation of cardiomyocytes is incomplete. Even after 5 months of culturing the cells, there were significant differences. Despite this limitation, the pictures of the cells were very impressive with beautiful cross striations.
Stem cells: unlocking the keys
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