Heart transplantation, a crucial intervention for saving lives of those with end-stage cardiac failure, often faces complications from acute allograft rejection. This study focuses on the intricate dynamics of immune cell interactions and specific communication pathways between organs, which are not yet well understood. Our study investigates this interplay using a murine heterotopic transplant model, using single-cell RNA sequencing to examine CD45+ immune cells from both the heart grafts and spleens. We conduct a comprehensive analysis focused on functional enrichment, cell trajectory, and interorgan communication in heart transplants, highlighting dynamic interactions between monocyte/macrophage subtypes that is mediated by extracellular vesicles (EVs). We use unsupervised clustering and elucidate the complex cellular interactions that influence allograft outcomes. Notably, we discovered that microRNA-363 and microRNA-709, carried by EVs from CD63+ graft macrophages, can induce M1 polarization within the recipient’s spleen via the Fcho2/Notch1 signaling pathway. These insights illuminate the nuanced immune responses during acute cardiac rejection and suggest that targeting EVs from graft-resident macrophages may offer a new strategy to mitigate transplant rejection.

中文翻译：

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移植物衍生的细胞外囊泡转运 miRNA 以调节心脏移植后巨噬细胞极化


心脏移植是挽救终末期心力衰竭患者生命的重要干预措施，经常面临急性同种异体移植物排斥反应的并发症。本研究侧重于免疫细胞相互作用的复杂动力学和器官之间的特定通信途径，这些尚不清楚。我们的研究使用小鼠异位移植模型调查了这种相互作用，使用单细胞 RNA 测序来检查来自心脏移植物和脾脏的 CD45+ 免疫细胞。我们进行了全面的分析，重点关注心脏移植中的功能富集、细胞轨迹和器官间通讯，突出了由细胞外囊泡 （EV） 介导的单核细胞/巨噬细胞亚型之间的动态相互作用。我们使用无监督聚类并阐明影响同种异体移植结果的复杂细胞相互作用。值得注意的是，我们发现 CD63 + 移植物巨噬细胞的 EV 携带的 microRNA-363 和 microRNA-709 可以通过 Fcho2/Notch1 信号通路在受体脾脏内诱导 M1 极化。这些见解阐明了急性心脏排斥反应期间细微的免疫反应，并表明靶向移植物驻留巨噬细胞的 EV 可能提供一种减轻移植排斥反应的新策略。