uncovered a previously unrecognized mode of cell competition between species during which “loser” human PS cells were eliminated via apoptosis by “winner” mouse PS cells (Zheng et al., 2021). However, whether cell competition plays any role during interspecies chimera formation has not been studied until recently.īy co-culturing human and mouse PS cells, Zheng et al. Cell competition has been implicated in safeguarding normal development and maintaining tissue homeostasis. Cell competition describes a fitness-sensing process during which “fitter” cells eliminate “loser” cells. However, whether human cell loss occurs via cell-autonomous and/or non-cell-autonomous process is unclear. To date, attempts to generate human-animal chimeric embryos have resulted in notably lower levels of chimerism than intra- and inter-species chimeras between mice and rats, indicating that human cells were eliminated during development. Ultimately, our poor understanding of human pluripotency warrants continued research along this line, thereby enabling the development of new culture conditions that further improve the chimera-competency of human PS cells in animals. It will be of interest to further understand the nature of human intermediate PS cell states in relation to human embryonic states accessible through extended ex vivo culture of human embryos. These studies also raise new questions regarding human pluripotency. It will be of great interest to assess the potential of human EPS cells to form interspecies chimeras gestated in utero, particularly with more distantly related livestock species such as pigs, the ideal animal host for organ generation. Nonetheless it remains unclear whether human EPS cells can generate interspecies chimeras when chimeric embryos are gestated in a uterus. While more studies are needed, it is possible that human EPS cells also reside in an intermediate state of pluripotency. A previous analysis of human EPS cells showed relatedness to primed PS cells and transcriptional distance from pre-implantation embryo cells and human naïve cells (Stirparo et al., 2018). Interestingly, a recent study analyzed the gene expression profile of mouse EPS cells and found that among different embryonic stages, stem cells grown in EPS cell conditions most closely corresponded to early post-implantation epiblast, a stage intermediate between naïve and primed pluripotency (Posfai et al., 2021). Following the introduction of human extended pluripotent stem (EPS) cells into monkey embryos, the EPS cell derivatives survived, proliferated, and generated different peri- and early post-implantation cell types (Yang et al., 2017 Tan et al., 2021). Of note, a recent study reported the identification of a human PS cell type competent for the generation of human-monkey ex vivo embryonic chimeras (Tan et al., 2021). The need for independent validation notwithstanding, these new studies raise the intriguing possibility that human intermediate PS cells are better suited for interspecies blastocyst complementation experiments.
Transcriptome analysis place some of these human naïve PS cells closer to E8-E10 than E6 human epiblast (Hu et al., 2020 Taei et al., 2020 Yu et al., 2020), suggesting they instead reside in intermediate rather than naïve pluripotency state. Interestingly, several naïve-like human PS conditions were recently reported, which supported the generation of human-mouse chimeric embryos (Hu et al., 2020 Taei et al., 2020). The same condition also supported derivation of horse PS cells, which contributed to chimera formation in E7 and E9 mouse embryos (Yu et al., 2020). In contrast, human PS cells with features characteristic of a pluripotency state in between naïve and primed pluripotency demonstrated interspecies chimera competency, albeit at low levels (Wu et al., 2017). Surprisingly, however, human naïve PS cells reportedly showed little to no chimeric contribution in mice, pigs, and even rabbit and monkey embryos (Theunissen et al., 2016 Wu et al., 2017 Aksoy et al., 2021) Based on studies in rodents, the capacity to form blastocyst chimeras has been thought to be confined to naïve pluripotency, which in part underlies the great efforts spent in the past decade to generate human naïve PS cells. Therefore, the developmental stage of donor cells might be critical for chimera formation. At the other end is primed PS cells that resemble peri-gastrulation epiblast and are capable of engrafting post-implantation epiblasts but not blastocysts. At one end of the spectrum is naïve PS cells with relatedness to pre-implantation epiblast and capacity to form chimeras upon introduction to blastocysts. Pluripotency in cultured PS cells spans across a spectrum of cellular states with distinct molecular and phenotypic features. However, only certain types of PS cells can form chimeras.
The generation of interspecies chimeras necessitate chimera competency of donor PS cells in the host species.