History, generation, application, and future of chimeras: A synthetic review

Abstract Chimeras, organisms with genetically distinct cells, offer opportunities to study genes and cellular mechanisms, and grow human organs in nonhuman animals for transplantation. The persistence and differentiation of donor cells depend on genetic and epigenetic factors during embryogenesis. Donor-host cell pairing, pluripotency, and lineage segregation affect cell integration, with poor results seen in intraspecies chimeras due to limited host tissue incorporation. In interspecies chimeras, evolutionary differences create a xenogeneic barrier. Strategies like gene editing, organogenesis gene overexpression in donor cells, and blocking host gene expression can overcome this barrier, potentially enabling the growth of human organs in nonhuman animals, and addressing organ shortages for transplantation. Stage pairing between the donor and host cells is one factor determining chimera formation. Early segregation of lineages in the inner cell mass (ICM), such as the differentiation of the primitive endoderm and primitive ectoderm can alter cell adhesion properties and capacity for donor cells to contribute to different cell populations of the fetus. When donor cells are in an epithelial state like the epiblast, they have distinct biological properties than those of the ICM. Appropriate development in the in vitro phase is a determinant of efficient chimera formation. The conditions in which the embryo develops must coincide with the conditions provided by the host species. The contribution of donor cells throughout the host fetus is impacted by the competition between donor porcine-induced pluripotent stem cells (iPSCs) and host stem cells for the same developmental niche. The most suitable approaches for organ generation are bioprinting, organoid technologies, and tissue engineering compared to interspecies chimeras and embryo models. Nevertheless, interspecies chimeras and embryo models hold potential for human organ development, which has been demonstrated in the generation of functional organs between rats and mice. Future attempts to produce human organs in nonhuman animals will likely be done in animals with less evolutionary distance. However, further studies will still be needed to overcome current technical and ethical barriers.