Cell competition constitutes a barrier for interspecies chimerism

Zheng, Canbin; Hu, Yingying; Sakurai, Masahiro; Pinzón-Arteaga, Carlos A.; Li, Jie; Wei, Yulei; Okamura, Daiji; Ravaux, Benjamin; Barlow, Haley R.; Yu, Lei; Sun, Hai Xi; Chen, Elizabeth H.; Gu, Ying; Wu, Jun

doi:10.1038/s41586-021-03273-0

Cited by 76 publications

(69 citation statements)

References 48 publications

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“…A species comparison between different types of hPSCs and pig embryonic cells showed broad equivalence ( Ramos-Ibeas et al., 2019 ), indicating that strategies to closely match hPSCs with the recipient embryos may enhance overall chimeric integration. Overexpression of an anti-apoptosis factor or modulation of signal related to cell competition resulted in increased chimera efficiency when rodent- or human-primed PSCs are injected into mouse blastocysts ( Masaki et al., 2016 ; Wang et al., 2018 ; Zheng et al., 2021 ). Preventing apoptosis using enhanced culture conditions can also improve interspecies chimerism between monkey and pig ( Fu et al., 2020 ).…”

Section: In Vitro Models For Early Development and The Germlinementioning

confidence: 99%

Conserved features of non-primate bilaminar disc embryos and the germline

2021

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Post-implantation embryo development commences with a bilaminar disc in most mammals, including humans. Whereas access to early human embryos is limited and subject to greater ethical scrutiny, studies on non-primate embryos developing as bilaminar discs offer exceptional opportunities for advances in gastrulation, the germline, and the basis for evolutionary divergence applicable to human development. Here, we discuss the advantages of investigations in the pig embryo as an exemplar of development of a bilaminar disc embryo with relevance to early human development. Besides, the pig has the potential for the creation of humanized organs for xenotransplantation. Precise genetic engineering approaches, imaging, and single-cell analysis are cost effective and efficient, enabling research into some outstanding questions on human development and for developing authentic models of early human development with stem cells.

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Section: In Vitro Models For Early Development and The Germlinementioning

confidence: 99%

Conserved features of non-primate bilaminar disc embryos and the germline

2021

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“…In this review, we summarized the advances and several hurdles in interspecies chimerism. As discussed, apoptosis is the first obstacle of hPSCs in interspecies chimerism, which could be a result of cell competition (31). The antiapoptosis ability is crucial for the chimera potential of both primed and naïve hPSCs (30).…”

Section: Discussionmentioning

confidence: 99%

“…The naïve hPSCs with high antiapoptosis competence possessed a high level of chimera formation efficiency (30). Recently, cell competition has been confirmed to be responsible to the apoptosis of primed hPSCs in the chimera, and overcoming the competition improved the survival and chimerism of human cells in early mouse embryos (31). These observations suggested that anti-apoptosis is a general property for cells that could form interspecies chimeras.…”

Section: Apoptosis Is the Initial Barrier In Interspecies Chimerism Of Hpscsmentioning

confidence: 95%

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

Li¹,

Huang²

2021

Stem Cell Investig

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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.

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“…To examine interspecies cell competition during early development, we have established an in vitro system based on co-culture of PSCs from different species. From these PSC co-culture experiments, it became evident that cell competition occurred between mouse and human cells in a dramatic fashion: most, if not all, human PSCs were actively sought after by mouse PSCs and died within a few days of co-culturing ( Zheng et al., 2021 ). This competitive interaction seems to be specific for primed pluripotency, as co-culturing human and mouse PSCs in naïve and differentiation conditions did not result in overt human cell death ( Fig.…”

Section: Cell Competition As a Barrier To Interspecies Chimerismmentioning

confidence: 99%

Fitness selection in human pluripotent stem cells and interspecies chimeras: Implications for human development and regenerative medicine

Barbaric

2021

Developmental Biology

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A small number of pluripotent cells within early embryo gives rise to all cells in the adult body, including germ cells. Hence, any mutations occurring in the pluripotent cell population are at risk of being propagated to their daughter cells and could lead to congenital defects or embryonic lethality and pose a risk of being transmitted to future generations. The observation that genetic errors are relatively common in preimplantation embryos, but their levels reduce as development progresses, suggests the existence of mechanisms for clearance of aberrant, unfit or damaged cells. Although early human embryogenesis is largely experimentally inaccessible, pluripotent stem cell (PSC) lines can be derived either from the inner cell mass (ICM) of a blastocyst or by reprogramming somatic cells into an embryonic stem cell-like state. PSCs retain the ability to differentiate into any cell type in vitro and, hence, they represent a unique and powerful tool for studying otherwise intractable stages of human development. The advent of PSCs has also opened up a possibility of developing regenerative medicine therapies, either through PSC differentiation in vitro or by creating interspecies chimeras for organ replacement. Here, we discuss the emerging evidence of cell selection in human PSC populations in vivo and in vitro and we highlight the implications of understanding this phenomenon for human development and regenerative medicine.

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Cell competition constitutes a barrier for interspecies chimerism

Cited by 76 publications

References 48 publications

Conserved features of non-primate bilaminar disc embryos and the germline

Conserved features of non-primate bilaminar disc embryos and the germline

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

Fitness selection in human pluripotent stem cells and interspecies chimeras: Implications for human development and regenerative medicine

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