BACKGROUND:Much of our knowledge of organ rejection after transplantation is derived from rodent models.METHODS:We used single-nucleus RNA sequencing to investigate the inflammatory myocardial microenvironment in human pediatric cardiac allografts at different stages after transplantation. We distinguished donor- from recipient-derived cells using naturally occurring genetic variants embedded in single-nucleus RNA sequencing data.RESULTS:Donor-derived tissue resident macrophages, which accompany the allograft into the recipient, are lost over time after transplantation. In contrast, monocyte-derived macrophages from the recipient populate the heart within days after transplantation and form 2 macrophage populations: recipient MP1 and recipient MP2. Recipient MP2s have cell signatures similar to donor-derived resident macrophages; however, they lack signatures of pro-reparative phagocytic activity typical of donor-derived resident macrophages and instead express profibrotic genes. In contrast, recipient MP1s express genes consistent with hallmarks of cellular rejection. Our data suggest that recipient MP1s activate a subset of natural killer cells, turning them into a cytotoxic cell population through feed-forward signaling between recipient MP1s and natural killer.CONCLUSIONS:Our findings reveal an imbalance of donor-derived and recipient-derived macrophages in the pediatric cardiac allograft that contributes to allograft failure.

中文翻译：

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人心脏同种异体移植物整个生命周期中的巨噬细胞景观

背景：我们对移植后器官排斥反应的了解大部分来自于啮齿类动物模型。方法：我们采用单核RNA测序技术研究人类小儿同种异体心脏移植物移植后不同阶段的炎症心肌微环境。我们利用单核 RNA 测序数据中嵌入的自然发生的遗传变异来区分供体来源的细胞和受体来源的细胞。结果：伴随同种异体移植物进入受体的供体来源的组织驻留巨噬细胞在移植后随着时间的推移而丢失。相比之下，来自受体的单核细胞来源的巨噬细胞在移植后几天内在心脏中聚集并形成 2 个巨噬细胞群：受体 MP1 和受体 MP2。受体 MP2 具有与供体来源的常驻巨噬细胞相似的细胞特征；然而，它们缺乏供体来源的常驻巨噬细胞典型的促修复吞噬活性特征，而是表达促纤维化基因。相比之下，受体 MP1 表达与细胞排斥特征一致的基因。我们的数据表明，受体 MP1 激活自然杀伤细胞的一个子集，通过受体 MP1 和自然杀伤细胞之间的前馈信号将它们转变为细胞毒性细胞群。结论：我们的研究结果揭示了供体来源和受体来源的巨噬细胞的不平衡。导致同种异体移植失败的儿科同种异体心脏移植物。