Human-animal interspecies chimerism via blastocyst complementation: advances, challenges and perspectives: a narrative review

Objective: Interspecific human-animal chimerism via blastocyst complementation provides a promising strategy to generate function human cells, tissues or organs from human pluripotent stem cells (hPSCs), although it is still quite challenging. In this review, we will mainly focus on the recent advances, such as the options of donor hPSCs and the understanding of interspecific chimera barriers, challenges, and perspectives on the efficient generation of human-animal interspecies chimeras. Background: hPSCs, including the human embryonic stem cells (hESCs) and the human induced pluripotent stem cells (hiPSCs) hold great promise for regenerative medicine to treat various degenerative diseases. However, although hPSCs can differentiate to all lineage cells in dish, the functionality of these cells is limited, hinting that the in vitro differentiation system failed to fully recapture the in vivo development. A promising alternative strategy is in vivo generation of functional human cells in animals through interspecies chimerism, based on the principle that mammalian development is highly conserved across species. This strategy was inspired by the successful generation of functional rat pancreas in mice through blastocyst injection of rat pluripotent stem cells (PSCs). Over the past ten years, since this milestone work was reported, advances have been made in the human-animal interspecies chimerism. However, it is still challenging to efficiently generate human cells, tissues, or organs in the interspecies chimeras. This phenomenon suggests that there are still obstacles to illustrate and overcome implicated in human-animal interspecies chimeras. Methods: Narrative overview of the literatures reported the recent advances, challenges and perspectives regarding the interspecies chimerism via blastocyst complementation. Conclusions: Human-animal interspecies chimerism via blastocyst complementation is a valuable method to generate functional human cells, tissues or organs, while there are at least three barriers need to be overcome. Firstly, conventional hPSCs should be converted to possess the chimera competency; secondly, efficient human-animal chimerism are required to robustly generate human derivatives in chimera; thirdly, the discrepancy regarding the developmental regulation network between human and host animals must be eliminated to generate certain human cells, tissues or organs in the interspecies chimeras.