Cross-species single-cell transcriptomic analysis reveals pre-gastrulation developmental differences among pigs, monkeys, and humans

Tianbin Liu,Leqian Yu,Ying Gu,Yong Li,Jie Li,Jun Wu,Guoyi Dong,Hai-Xi Sun,Yue Shen,Yingying Hu,Jing Li

doi:10.1038/s41421-020-00238-x

Abstract

Interspecies blastocyst complementation enables organ-specific enrichment of xenogeneic pluripotent stem cell (PSC) derivatives, which raises an intriguing possibility to generate functional human tissues/organs in an animal host. However, differences in embryo development between human and host species may constitute the barrier for efficient chimera formation. Here, to understand these differences we constructed a complete single-cell landscape of early embryonic development of pig, which is considered one of the best host species for human organ generation, and systematically compared its epiblast development with that of human and monkey. Our results identified a developmental coordinate of pluripotency spectrum among pigs, humans and monkeys, and revealed species-specific differences in: (1) pluripotency progression; (2) metabolic transition; (3) epigenetic and transcriptional regulations of pluripotency; (4) cell surface proteins; and (5) trophectoderm development. These differences may prevent proper recognition and communication between donor human cells and host pig embryos, resulting in low integration and survival of human cells. These results offer new insights into evolutionary conserved and divergent processes during mammalian development and may be helpful for developing effective strategies to overcome low human–pig chimerism, thereby enabling the generation of functional human organs in pigs in the future.

Highlights

Shortage of human organs for transplantation represents one of the largest unmet medical needs worldwide, which is expected to increase
With regard to human and pig blastocyst complementation, accumulating evidence have shown that human pluripotent stem cell (PSC) inefficiently contributed to chimera formation in early pig embryos (E21–E28) and the level of chimerism was far lower than that between rat and mouse, regardless of pluripotent states, injection timing and number of cells injected[10]
By filtering differentially expressed genes (DEGs) (Pre-EPIs versus PostEPIs) through the transcription factors (TFs) and cofactor data in Animal TFDB, we found that MBD, NF-YA and STAT TF families were enriched in pig Pre-EPIs, while homeobox TF family was and highly expressed in monkey and human Pre-EPIs (Supplementary Fig. S4h)

Summary

Introduction

Shortage of human organs for transplantation represents one of the largest unmet medical needs worldwide, which is expected to increase. With regard to human and pig blastocyst complementation, accumulating evidence have shown that human PSCs inefficiently contributed to chimera formation in early pig embryos (E21–E28) and the level of chimerism was far lower than that between rat and mouse, regardless of pluripotent states, injection timing and number of cells injected[10]. These results indicate a major xenogeneic barrier exists between human and pig during early embryogenesis

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Results

Conclusion