Researchers at the Institute of Science Tokyo, Japan, announced on July 31 that blocking xenophagocytosis—a natural immune process—improves donor cell survival and enables more effective interspecies organ generation. The team developed strategies to prevent embryonic macrophages from eliminating living donor cells, which led to significantly improved survival rates for these cells and successful generation of rat pancreas in mice.
Organ transplantation has saved many lives, but a shortage of donor organs remains a significant challenge. Blastocyst complementation, which uses stem cells to grow organs inside embryos of another species, is a promising strategy; however, its efficacy is limited because most donor cells do not survive early embryonic development.
The research team, led by Specially Appointed Honorary Professor Hiromitsu Nakauchi from the Stem Cell Therapy Laboratory at the Institute of Integrated Research (Science Tokyo), collaborated with Stanford University researchers to investigate why donor cells are rapidly eliminated during blastocyst complementation. Their findings were published online in Cell on June 5. They found 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," said Nakauchi.
To study this mechanism, the researchers used mouse–rat chimeric embryos and observed that rat stem cells injected into mouse embryos experienced cellular stress exposing phosphatidylserine—an "eat-me" signal—on their surface. Primitive macrophages recognized this signal through the Axl receptor and engulfed otherwise healthy donor cells before adaptive immunity formed.
The team then developed three strategies: genetically depleting host macrophages or disrupting Axl receptors; engineering donor cells to express CD47 (a "don't eat-me" signal); and increasing ATP11C activity to prevent phosphatidylserine exposure. Each approach improved donor cell survival and increased success rates for generating rat pancreas in mice. The same immune response was seen in human-to-mouse chimeras, where reducing host macrophages improved human cell survival as well. "Controlling xenophagocytosis significantly improved donor cell engraftment and organ generation, providing a new strategy for overcoming a major biological barrier to regenerative medicine," said Nakauchi.
The study identifies xenophagocytosis as an innate immune mechanism preserving species boundaries during embryonic development while offering practical solutions for advancing interspecies blastocyst complementation toward producing transplantable human organs.
