From Gene Editing to Exogenesis: Pigs as a Source of Immune-compatible Organs for Transplantation

The persistent shortage of human organs for transplantation has intensified efforts to develop alternative sources, specifically xenotransplantation and exogenesis. Xenotransplantation uses genetically engineered pigs to provide organs, tissues, and cells for clinical use. Significant progress has occurred in developing multigene-modified pigs that lack glycan xenoantigens while expressing human complement and coagulation regulators. These modifications have successfully mitigated hyperacute, antibody-mediated, and cellular rejection in preclinical nonhuman primate models. Recent compassionate-use cases in humans have demonstrated the feasibility of heart, kidney, and liver xenotransplantation, although achieving long-term survival remains a challenge. Complementing this approach, exogenesis aims to generate human-compatible organs within animal hosts through interspecies chimerism. Although advances in establishing organ niches and overcoming xeno-barriers have yielded preliminary success in heart, pancreas, and muscle development, formidable immune and developmental hurdles remain. Together, these approaches offer promising strategies to expand the donor organ pool and address the growing global demand for transplantation. Further advances in genetic engineering, immune modulation, and developmental biology, supported by rigorous preclinical and clinical evaluation, will be critical for widespread translation. This review outlines the current progress, major challenges, and future directions in xenogeneic and exogenic organ generation.