Interspecies chimeras for human stem cell research

Abstract

Interspecies chimeric assays are a valuable tool for investigating the potential of human stem and progenitor cells, as well as their differentiated progeny. This Spotlight article discusses the different factors that affect interspecies chimera generation, such as evolutionary distance, developmental timing, and apoptosis of the transplanted cells, and suggests some possible strategies to address them. A refined approach to generating interspecies chimeras could contribute not only to a better understanding of cellular potential, but also to understanding the nature of xenogeneic barriers and mechanisms of heterochronicity, to modeling human development, and to the creation of human transplantable organs.

Matched Developmental Timing of Donor Cells with the Host Is Crucial for Chimera Formation

“…Thus, the question whether current naive human PSCs are chimera competent and are developmentally equivalent to the mouse blastocyst remains unresolved. Moreover, other parameters such as the proliferation rate of the donor cells, or the evolutionary distance between the host and injected cells serve as a barrier for interspecies chimera formation ( Cohen et al., 2016 , Masaki and Nakauchi, 2017 , Wu et al., 2016 ).…”

“…Chimeric animals are typically generated from cells of more than one individual and can be produced by mixing of early embryos ( Gardner, 1968 , Mintz, 1962 , Tarkowski, 1961 ) or by engrafting cells or tissues into embryos at different stages of development ( Le Douarin and Teillet, 1973 ). In addition to being useful tools for the study of development, the generation of interspecies human-animal chimeras has been proposed as a source of human cells and organs for regenerative medicine ( Masaki and Nakauchi, 2017 , Wu et al., 2017 ). To define the parameters that promote functional engraftment of donor cells into embryos and chimera formation is important for the generation of interspecies chimera models.…”

Design Approaches for Generating Organ Constructs

“…Compared with traditional chimeras that are highly random, chimeric complementation is a strategy that can selectively enrich chimerism in the target organ/tissue (Kobayashi et al, 2010;Suchy et al, 2018;Wu and Izpisua Belmonte, 2015). It is now highly feasible to delete specific types of cells via conditionally deleting essential genes or direct ablation of specific cells to create a niche for the organ/tissue of interest (Masaki and Nakauchi, 2017;Suchy and Nakauchi, 2017;Wu and Izpisua Belmonte, 2015). Hypothetically, introduction of PSCs into the defective embryo could fill up the created niche by differentiating into the deleted cells.…”

Humanization of Immunodeficient Animals for the Modeling of Transplantation, Graft Versus Host Disease, and Regenerative Medicine

“…For these models, the rat is often used. 236 , 237 Nevertheless, species chimerism decreases with time during the embryo development and this could be due to in embryo immune responses, including SIRPα-CD47 incompatibilities that could benefit from the use of SIRPα humanized rats. Additionally, a number of rat knockout models that reproduce human genetic diseases better than mice, such as in dystrophin 238 or Aire -deficient 239 rats, could be used in an immunodeficient-humanized setting.…”