In vivo tissue engineering of patient specific chimeric liver tissue for wholeorgan liver transplantation

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Annually, more than 70.000 patients in Europe die fi'om various forms of liver failure. For some liver diseases cell based therapies, tissue engineering or gene therapies are being developed, but the majority of patients will require a transplantable organ for ultimate cure. Xenotransplantation of porcine organs is promising for kidney, heart or pancreas (islets), and significant progress hasbeen made in controlling the immunological rejection by using organs fi'om multi-transgenic pigs. The porcine liver, however, is largely incompatible with the human physiology.Repopulation of a xenogeneic liver by the patient's own cells could thus be promising to adapt the organ to a particular patient. Here, we propose to use blastocyst injection of induced pluripotent stem cells (iPSCs) to generate recipient derived liver chimeras in mice and rats. In a novel organ transplantation animal model we will analyze the fijnctionality and cellular adaptation of chimerized livers with allogeneic and xenogeneic scaffolds. We will employ immunosuppressive strategies and analyze the degree of recipient derived cellular substitution, long term fijnction and possible tolerance induction. In parallel to experiments with laboratory animals, we will inject monkey and human iPS cells into GAL"^"/FAH"'"porcine blastocysts to produce a large chimeric animal as an important step for translation of the chimeric liver concept towards clinical application.