2. Academic Validation
  3. Xenophagocytosis blockade enhances interspecies chimerism

Xenophagocytosis blockade enhances interspecies chimerism

  • bioRxiv. 2025 Oct 15:2025.10.14.682291. doi: 10.1101/2025.10.14.682291.
Sicong Wang 1 2 3,  Kouta Niizuma 1 2 3,  Daniel Dan Liu 1 4 3,  Fabian P Suchy 1 2,  Hideyuki Sato 5,  Ayaka Yanagida 6,  Hideki Masaki 5,  Masashi Miyauchi 1 2,  Saman Tabatabaee 1 7,  Nathan Hidajat 1 2,  Joydeep Bhadury 1 2,  Carsten T Charlesworth 1 2,  Jinyu Zhang 1 2,  Irving L Weissman 1 4,  Hiromitsu Nakauchi 1 2 5 8
Affiliations

Affiliations

  • 1 Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 3 These authors contributed equally.
  • 4 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 5 Stem Cell Therapy Laboratory, Institute of Integrated Research, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  • 6 Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
  • 7 Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 8 Lead Contact.
PMID: 41279269 DOI: 10.1101/2025.10.14.682291
Abstract

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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