A team from the Institute of Science Tokyo (in collaboration with Stanford University) has made a significant breakthrough in regenerative medicine. They identified a previously unknown immune mechanism called xenophagocytosis that drives the rapid rejection of donor cells during interspecies organ generation. In this process, embryonic macrophages actively engulf and eliminate living donor cells from another species. eurekalert.org +1
The researchers studied mouse–rat chimeric embryos, where rat stem cells (donor cells) were injected into mouse embryos. They discovered that when donor cells are placed in a foreign embryonic environment, they experience cellular stress. This stress causes phosphatidylserine, an «eat-me» signal that is normally hidden within the cell membrane, to become exposed on the cell surface. Primitive macrophages then recognize this signal through the Axl receptor, leading them to engulf the otherwise healthy donor cells — even before the adaptive immune system has formed.
Having uncovered this mechanism, the team developed three complementary strategies to overcome the barrier:
- Genetically depleting host macrophages or disrupting the Axl receptor.
- Engineering donor cells to express CD47, a «don’t eat-me» signal that helps them evade attack.
- Increasing the activity of the ATP11C protein, which prevents phosphatidylserine from appearing on the cell surface.
Each approach significantly improved donor cell survival. Moreover, the team observed the same immune response in human-to-mouse chimeras, and reducing host macrophages markedly improved the survival of human donor cells. This finding not only reveals a fundamental innate immune mechanism that helps preserve species boundaries during early development but also provides practical strategies to advance interspecies blastocyst complementation — a key step toward growing functional organs for transplantation.
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