Abstract

Much of our knowledge of organ rejection after transplantation is derived from rodent studies. We used single-nucleus RNA sequencing (snRNA-seq) to investigate the inflammatory milieu in pediatric cardiac allografts at different stages post transplantation. We distinguished donor from recipient-derived cardiac cells using naturally occurring genetic variants embedded in snRNA-seq data. Donor-derived cardiac resident macrophages dMPs, which accompany the cardiac allograft into the recipient, are rapidly lost post transplantation. On the other hand, monocyte-derived macrophages from the recipient (rMPs) quickly populate the heart post transplantation and form two macrophage populations, rMP1 and rMP2. While rMP2s have cell signatures similar to dMPs, they lack pro-reparative phagocytic activity and instead express profibrotic genes. In contrast, rMP1 express genes consistent with hallmarks of cellular rejection. Our data further support the conclusion that rMP1s activate a subset of natural killer (NK) cells, turning them into a cytotoxic cell population. Self-amplifying reciprocal signaling occurs between rMP1s and NKs, which is consistent with a key mechanism for clinical rejection. Our data reveal an imbalance of donor-derived and recipient-derived macrophages in the pediatric cardiac allograft after heart transplantation. Moreover, we observed a clear functional dichotomy of recipient-derived macrophages. At different stages after heart transplantation, rMPs contribute to acute adverse damage to the myocardium and chronic organ failure.

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