Immunological acceptance of embryonic stem cell-derived cardiomyocytes by imitating fetomaternal tolerance

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Todays most urgent problem in transplantation is the increasing shortage of suitable donor organs and tissues. One possible alternative to organ transplantation may be cell therapy, whereby the aim is to replace, repair, or enhance the biological function of the diseased organ or damaged tissue.Autologous, patient-specific adult stem cells are currently under investigation. Because they are derived directly from the same patient they will be used in, they are not subject to immune rejection. However, the efficacy of adult stem cells is still under debate, especially for myocardial regeneration. Engraftment is low or absent and the effect via paracrine mechanisms transient. Indeed, there is no actual regeneration of myocardium. We and others firmly believe that pluripotent stem cells, such as human embryonic stem (hES) cells will eventually be necessary to achieve real tissue regeneration. hES cells, however, cannot be patient-specific, but are allogeneic and inevitably induce immune rejection. Cellular grafts (in contrast to solid organs) lend themselves exceptionally well to pre-transplantation in vitro genetic engineering. We therefore propose to characterize the immunophenotype of hES cells during differentiation and after transplantation (aim 1), to generate hypo-immunogenic hES cells that induce tolerance (aim 2) and to describe xenogeneic immune responses in comparison to hES cells in vivo. The strategies adapted from fetomaternal tolerance to (1) prevent T cell mediated hES cell lysis, to (2) attract Tregs, and to (3) prevent macrophage and NK cell mediated hES cell lysis will first be employed individually and tested in target-cell specific immune assays. Later, the three strategies will be combined to generate a hypo-immunogenic hES cell line and the most promising tolerogenic combination will be validated in an allogeneic, humanized mouse model. Finally, we are aiming to generate hypo-immunogenic hES cell-derived cardiomyocytes and test their therapeutic potential in a myocardial infarction model (aim 3). Hypo-immunogenic hES cell-derived cardiomyocytes will be transplanted into the ischemic border zone of humanized mice that underwent permanent LAD ligation. Long-term cell survival and improvement of cardiac function will be assessed using multiple cutting edge imaging modalities (BLI, echo, microCT).The information gained in this study will be important in guiding the use of hES cells as a clinical treatment for human diseases in the future.