Researchers at the Institute of Science Tokyo and Stanford University have identified a previously unrecognized immune mechanism that rapidly eliminates donor cells during interspecies organ generation. The process, named “xenophagocytosis,” occurs when embryonic macrophages engulf living cells from another species before those cells can contribute to the development of a replacement organ. By blocking this response, the scientists substantially improved donor-cell survival and increased the production of rat pancreases inside mouse embryos. The findings, published in Cell, could help overcome one of the most persistent barriers to growing transplantable organs in animals.
Organ transplantation has transformed modern medicine, but the supply of donor organs remains far below global demand. Researchers have therefore explored blastocyst complementation, a technique in which pluripotent stem cells from one species are introduced into an early embryo of another species. If the host embryo lacks the genetic instructions required to form a particular organ, donor cells can potentially fill that developmental niche and generate the missing tissue. Experiments in animals have demonstrated that this approach can produce organs such as pancreases, kidneys, and livers. However, donor cells are often lost soon after introduction, sharply limiting the efficiency of the method.
To investigate this early cell loss, a team led by Specially Appointed Honorary Professor Hiromitsu Nakauchi examined mouse–rat chimeric embryos. In these experiments, rat stem cells were injected into mouse embryos and monitored during early development. The researchers discovered that many donor cells were not dying passively or being rejected by the adaptive immune system. Instead, they were actively recognized and swallowed by primitive macrophages, immune cells that appear in embryos before a fully developed adaptive immune system is present.
The process begins when donor cells encounter the foreign biochemical environment of the host embryo. This interspecies setting generates cellular stress, which causes phosphatidylserine to become exposed on the outer surface of the donor-cell membrane. Phosphatidylserine is normally confined to the inner layer of the plasma membrane, but its external exposure functions as an “eat-me” signal. In healthy tissues, this signal commonly marks dying or damaged cells for removal. In the chimeric embryos, however, it appeared on living donor cells that were still capable of contributing to organ development.
Embryonic macrophages detected the exposed phosphatidylserine through Axl, a receptor involved in the recognition and clearance of cellular material. Once activated, the macrophages engulfed the donor cells through a process resembling phagocytosis, despite the fact that the cells were alive. This distinction is important because conventional descriptions of immune rejection generally focus on adaptive immune responses or the destruction of foreign cells by antibodies and lymphocytes. Xenophagocytosis appears to act much earlier, creating an innate immune barrier before those later immune components have matured.
The researchers tested several ways to interrupt this response. In the host embryos, they either depleted macrophages genetically or disrupted the gene encoding Axl, thereby reducing the immune system’s ability to recognize and engulf donor cells. In a complementary strategy, the scientists modified donor cells to express CD47, a membrane protein that delivers a “don’t eat-me” signal to macrophages. CD47 interacts with macrophage receptors and can suppress engulfment, allowing donor cells to remain in tissues that would otherwise remove them.
A third approach targeted the donor cells’ membrane biology. The researchers increased the activity of ATP11C, an enzyme that helps maintain phospholipid asymmetry by moving phosphatidylserine away from the outer membrane surface. By limiting phosphatidylserine exposure, ATP11C reduced the appearance of the molecular signal that triggered macrophage attack. Each intervention improved donor-cell survival, and combining immune modulation with donor-cell engineering produced a substantial increase in interspecies chimerism.
The biological effect was especially significant in experiments designed to generate rat pancreases in mice. Suppressing xenophagocytosis increased the number of surviving rat cells and improved the likelihood that they would populate the developing pancreatic region. The team also detected a similar response in human-to-mouse chimeric models. Reducing host macrophages improved the persistence of human donor cells, suggesting that the mechanism may operate across several species combinations rather than being limited to the mouse–rat system.
The discovery identifies xenophagocytosis as both a fundamental developmental mechanism and a practical obstacle to regenerative medicine. It suggests that species boundaries may be reinforced not only by genetic incompatibility but also by innate immune surveillance that removes foreign living cells at the earliest stages of development. Nevertheless, the work remains an experimental demonstration in animal embryos. Translating the approach toward human organ generation will require careful evaluation of safety, immune regulation, developmental compatibility, ethical concerns, and the risk that manipulating macrophages could impair normal tissue development or increase susceptibility to infection. The researchers now aim to determine precisely how xenogeneic environments create cellular stress and whether additional methods can protect donor cells without disrupting embryonic health. Their findings provide a new molecular target for improving blastocyst complementation and bring scientists closer to the long-term goal of producing functional organs for transplantation.
Subject of Research: Animals
Article Title: Xenophagocytosis blockade enhances interspecies chimerism
News Publication Date: 5-Jun-2026
Web References: https://doi.org/10.1016/j.cell.2026.05.016
References: Cell, DOI: 10.1016/j.cell.2026.05.016
Image Credits: Institute of Science Tokyo
Keywords
Xenophagocytosis, interspecies chimerism, blastocyst complementation, organ generation, macrophages, phosphatidylserine, Axl receptor, CD47, ATP11C, regenerative medicine, organ transplantation, stem cells
