This article was published online in the journal Cell Stem Cell by researchers at the University of Texas Southwestern Medical Center on August 23.

Incompatibilities in cell adhesion pose a barrier to interspecies chimerism

Innovation and novelty of the article

Focus on cell adhesion incompatibility: This study specifically pointed out that cell adhesion incompatibility is an important obstacle facing xenogeneic chimeras, which has not been fully explored in past research. By highlighting this aspect, the authors provide a clearer understanding of the challenges encountered when integrating pluripotent stem cells (PSCs) from different species.

Innovative synthetic biology approaches: Researchers have developed a novel synthetic biology strategy to enhance cell adhesion between species through nanobody-antigen interactions. This approach represents a major improvement over traditional techniques because it can target improved cell adhesion between species without disrupting natural cell connections or signaling pathways.

Empirical verification of technology: The study used multiple cell adhesion testing methods, including modified two-cell flow cytometry and elution experiments, to quantitatively assess the effectiveness of their strategy. This rigorous methodology provides strong evidence for the improved adhesion of xenogeneic PSC achieved through its synthetic strategy.

Potential for widespread application: By demonstrating that their synthetic cell adhesion system can improve the chimerism contribution of human PSC in mouse embryos, the authors suggest that this approach may open up new possibilities for cross-species organogenesis, which is a major step forward in addressing global organ shortages.

Addressing limitations of previous studies: The article acknowledges some limitations in previous studies, such as xenogeneic disorders and the dynamics of cell adhesion molecule expression during development. By proposing a solution that circumvents these problems, the authors contribute to a more comprehensive understanding of xenogeneic chimeras.

Overall, this paper builds on the work of predecessors and solves long-standing challenges in the field of xenogeneic chimeras by providing new insights and innovative solutions.

Article analysis

Background: Heterogeneous embryo sac complementation technology is a promising strategy to address global organ shortages by growing human organs in animal hosts. However, achieving effective chimerism of human pluripotent stem cells (PSCs) in evolutionarily distant species is hindered by various xenogeneic barriers, especially cell adhesion incompatibilities. Although previous studies have identified barriers such as cell competition and development timing, the role of cell adhesion in them has not been thoroughly studied.

Advanced methods: The authors have developed a synthetic biology method that uses nanoantibody-antigen interactions to enhance xenogeneic cell adhesion. They engineered PSCs to express specific nanobodies and their corresponding antigens on the cell surface, significantly improving the adhesion between human and animal PSCs in vitro experiments. The method has been validated through multiple cell adhesion tests, including two-cell and elution tests, demonstrating its effectiveness in overcoming adhesion barriers without disrupting natural cell functions.

Research results:

Cell adhesion incompatibility is a significant barrier to xenogeneic chimeras, especially among evolutionarily distant species.

The synthetic nanoantibody mediated cell adhesion system significantly improved the adhesion of human and mouse PSCs in vitro.

In vivo experiments have shown that this method increases the contribution of human PSCs to mouse embryos, indicating enhanced chimerism.

Conclusion: Studies have shown that cell adhesion incompatibility is one of the key xenogeneic barriers preventing the formation of successful xenogeneic chimeras. The synthetic biology strategy developed in this study provides a promising solution to enhance the adhesion of xenogeneic cells and may help in the cultivation of human organs in animal models, thereby addressing the organ shortage crisis.

Research limitations:

This research is limited to the use of a single nanobody sequence (vhhGFP4), and further studies are needed on the effectiveness of using nanobodies with different affinities to regulate adhesion strength.

The GPI anchoring used to localize nanobodies on the surface is not attached to the cytoskeleton, making it susceptible to mechanical shedding or enzymatic hydrolysis.

Research focuses on specific species combinations, and the universality of the research results to other species or wider organogenic applications needs to be explored.