Organ transplantation is an efficient approach or remedying end-life diseases that cannot be treated by other methods. Nevertheless, the available organs do not cover the clinical demand. As an alternative to the transplantation human organs, the xenotransplantation of animals’ organs has been proposed. Unfortunately, despite the big effort of the last decades, organs are severely rejected upon xenotransplantation, the endothelial cells (ECs) playing a fundamental role in this process. ECs are the first target of the immune system reactions; moreover molecular incompatibilities between host’s coagulation system and the exogenous ECs enhance thrombotic microangiopathy, which rapidly destroys the xenotransplanted organ. Therefore, we hypothesize that endotheliarization of the donor’s organs with cells of the future host may have an important effect on the rejection upon xenotransplantation. To prove this hypothesis, we propose to generate (mouse-ratEC) chimera by inter-species blastocyst complementation assay, which recently has been described effective for the generation of chimera animals between different species, and to determine the degree of rejection against the hearts of this chimera, once heterotopically xenotransplanted in rat. This project, which is based on mouse and rat systems, aims to deliver a proof of principle that, if obtained, will be further developed in clinically more relevant big animal models.