Xenophagocytosis is a natural immune process that limits interspecies organ generation by eliminating living donor cells, report researchers at Institute of Science Tokyo, Japan. By uncovering how embryonic macrophages eliminate living donor cells, the researchers developed strategies to block this response. Using this strategy, they significantly improved donor cell survival and generation of rat pancreas in mice, bringing us one step closer to producing transplantable human organs in animals.
Organ transplantation has saved thousands of lives. However, the shortage of donor organs continues to be one of the greatest challenges in transplantation medicine, leaving many patients waiting for life-saving treatments. One promising strategy is blastocyst complementation, a technique that uses stem cells to grow organs inside the embryos of another species. Although this approach has been proven successful for the generation of organs in experimental animals, its efficacy remains limited because most donor cells often fail to survive during early embryonic development.
To investigate this, a research team led by Specially Appointed Honorary Professor Hiromitsu Nakauchi from the Stem Cell Therapy Laboratory, Institute of Integrated Research, Institute of Science Tokyo (Science Tokyo), Japan, in collaboration with researchers at Stanford University, USA, set out to determine the mechanism by which donor cells are rapidly eliminated during blastocyst complementation. Their findings, made available online in the journal Cell on June 5, 2026, reveal that early macrophages in embryos actively engulf living donor cells.
"Xenophagocytosis describes how embryonic macrophages eliminate living donor cells from another species. By blocking this process, we aimed to improve donor cell survival," explains Nakauchi.
To uncover this mechanism, the team studied mouse–rat chimeric embryos in which rat stem cells (donor cells) were injected into mouse embryos. They found that when the donor cells are placed in a foreign embryonic environment, they experience cellular stress that causes phosphatidylserine, an "eat-me" signal to become exposed on the cell surface. This signal is normally hidden within the cell membrane. When exposed, primitive macrophages recognize this signal through the receptor Axl, leading them to engulf otherwise healthy donor cells before the adaptive immune system has even formed.
After uncovering the mechanism, the researchers developed three complementary strategies to overcome this barrier. First, the researchers reduced the host's ability to eliminate donor cells by genetically depleting host macrophages or disrupting the Axl receptor, both of which are involved in xenophagocytosis. Second, they engineered the donor cells to express CD47, a "don't eat-me" signal that helps the cells evade attack by host macrophages. Thirdly, they increased the activity of ATP11C, a protein that prevents phosphatidylserine from appearing on the cell surface, thereby reducing the signals that trigger macrophages to engulf donor cells.
Each of these approaches significantly improved donor cell survival. Impressively, suppressing xenophagocytosis substantially increased the success rate of generating rat pancreas in mice. Moreover, the team also observed the same immune response in human-to-mouse chimeras in which reducing host macrophages markedly improved the survival of human donor cells. "Controlling xenophagocytosis significantly improved donor cell engraftment and organ generation, providing a new strategy for overcoming a major biological barrier to regenerative medicine," notes Nakauchi.
The significance of the study lies in the recognition of xenophagocytosis, which is a previously unrecognized innate immune mechanism that helps preserve species boundaries during early embryonic development. Beyond revealing this fundamental mechanism, the study also offers practical strategies for improving interspecies blastocyst complementation, an essential step toward growing functional organs for transplantation.
In the future, the researchers aim to focus on understanding how xenogeneic environments trigger cellular stress and whether additional approaches can further enhance donor cell survival. Combining immune modulation with advances in stem cell technology and organ generation, researchers hope to develop reliable methods for producing transplantable human organs, helping address the global shortage of donor organs and advancing regenerative medicine.
