Journal Article10.1016/j.stem.2024.07.010
Incompatibility in cell adhesion constitutes a barrier to interspecies chimerism
Emily Ballard,Masahiro Sakurai,Leqian Yu,Lizhong Liu,Seiya Oura,Jia Huang,Fan Guo +6 more
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TL;DR: Researchers developed a synthetic biology strategy to enhance interspecies cell adhesion by leveraging nanobody-antigen interactions, significantly improving chimerism of human pluripotent stem cells in animal hosts, addressing a major barrier to interspecies organ transplantation.
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Abstract: Interspecies blastocyst complementation holds great potential to address the global shortage of transplantable organs by growing human organs in animals. However, a major challenge in this approach is the limited chimerism of human cells in evolutionarily distant animal hosts due to various xenogeneic barriers. Here, we reveal that human pluripotent stem cells (PSCs) struggle to adhere to animal PSCs. To overcome this barrier, we developed a synthetic biology strategy that leverages nanobody-antigen interactions to enhance interspecies cell adhesion. We engineered cells to express nanobodies and their corresponding antigens on their outer membranes, significantly improving adhesion between different species' PSCs during in vitro assays and increasing the chimerism of human PSCs in mouse embryos. Studying and manipulating interspecies pluripotent cell adhesion will provide valuable insights into cell interaction dynamics during chimera formation and early embryogenesis.
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Citations
Xenophagocytosis blockade enhances interspecies chimerism
Sicong Wang,Kouta Niizuma,Daniel Dan Liu,Fabian P. Suchy,Hideyuki Sato,Ayaka Yanagida,Hideki Masaki,Masashi Miyauchi,Saman Tabatabaee,Nathan Hidajat,Joydeep Bhadury,Carsten T. Charlesworth,Jinyu Zhang,Irving L Weissman,Hiromitsu Nakauchi,Sicong Wang,Kouta Niizuma,Daniel Dan Liu,Fabian P. Suchy,Hideyuki Sato,Ayaka Yanagida,Hideki Masaki,Masashi Miyauchi,Saman Tabatabaee,Nathan Hidajat,Joydeep Bhadury,Carsten T. Charlesworth,Jinyu Zhang,Irving L Weissman,Hiromitsu Nakauchi,Fabian P. Suchy,Carsten T. Charlesworth,Irving L Weissman +32 more
- 15 Oct 2025
Abstract: SUMMARY Organ shortage remains a major challenge in transplantation medicine. Interspecies blastocyst complementation is a promising approach to generate human organs in livestock hosts. However, getting xenogeneic donor cells to engraft and expand at early stages remains challenging. Here we identify an innate immune barrier, wherein host macrophages selectively recognize and eliminate viable xenogeneic donor cells. These events represent a form of phagoptosis and highlight a xenogeneic clearance process that we term xenophagocytosis. We identify the mechanism by which host macrophages selectively phagocytize xenogeneic donor cells: xenogeneic cells display elevated phosphatidylserine, an “eat-me” signal recognized by host macrophages through phagocytic receptor Axl. Xenophagocytosis blockade improves both rat and human donor chimerism in mouse embryos, indicating a conserved mechanism. These findings reveal potential mechanisms by which innate immune cells eliminate xenogeneic cells in early embryogenesis to preserve species integrity and offer improved strategies for generating human organs in livestock.
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