TRANSLATING HUMAN EMBRYONIC STEM CELL-DERIVED ENDOTHELIAL CELL THERAPY TO THE CLINIC

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Human embryonic stem (hES) cells and induced pluripotent stem cells (iPS) hold broad potential in regenerative medicine. Such cells can generate all cell types upon stimulation to differentiate along defined cell commitment pathways. We are interested in the mechanisms that govern stimulation of these cells into vascular endothelial cells and their subsequent application to regenerative medicine. These cells line all blood vessels and have the capacity to induce blood vessel growth upon injection into the body. We have recently published a study that shows the potential of human endothelial cells derived from human embryonic stem cells (Kane et al., ATVB, 2010). We showed a very efficient production of endothelial cells in just 10 days following initiation of differentiation from the original hES cells. This rapid system induced robust changes, i.e. very effective reduction in pluripotency markers and induction of endothelial selective markers. We also defined the "therapeutic" potential of these cells in cell cultures and in animal models by demonstrating the induction of new blood vessel growth leading to better blood flow in the muscle that was damaged. The induction of this phenotype suggests that these cells and this differentiation system may be useful clinically in the treatment of ischemic conditions in patients with cardiovascular disease. In previous funding that ended recently, we were able to produce endothelial cells from hES cells at clinical grade thus showing proof of concept that these cells can be produced at the quality and quantity required for potential clinical use. This is a powerful approach that has not been tested in man yet. This is our aim for the present grant application.In this proposal we will address a very important issue that now is required for further development of this product towards a first application in man. We require this grant funding to complete development of the cells at a grade acceptable for clinical use. We will further refine the protocol for production, fully test the cells produced in cell culture and by detailed analysis. We will then test the safety the cells and how good they are at inducing blood vessel growth in two important animal models, in mouse and rabbit. Finally, we will assess where the cells go after injection looking at retention in the tissue, dissemination to other tissues and organs and how long they stay there. These are important issues that will allow us to gain regulatory approval if the grant is successful.