人类肝移植图谱揭示了一种与早期移植物功能不全发生相关的致病免疫生态位

Xin Shao, Zheng Wang, Kai Wang, Xiaoyan Lu, Ping Zhang, Rongfang Guo, Jie Liao, Penghui Yang, Shusen Zheng, Xiao Xu, Xiaohui Fan

工程（英文） ›› 2024, Vol. 36 ›› Issue (5) : 193-208.

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工程（英文） ›› 2024, Vol. 36 ›› Issue (5) : 193-208. DOI: 10.1016/j.eng.2023.12.004
研究论文
Article

人类肝移植图谱揭示了一种与早期移植物功能不全发生相关的致病免疫生态位

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A Single-Cell Landscape of Human Liver Transplantation Reveals a Pathogenic Immune Niche Associated with Early Allograft Dysfunction

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摘要

肝移植是终末期肝病患者的标准治疗方法。尽管肝移植技术取得了显着进步，但术后早期移植物功能不全（early allograft dysfunction, EAD）的发生会对受者的预后产生不利影响，加剧了当前器官短缺的现状，仍然是一个严重的临床问题。然而，肝脏组织的细胞异质性阻碍了人们对EAD发生的细胞特征和分子事件进行准确表征。为此，本研究从7个患者中收集了来自冷缺血和缺血再灌注两个阶段的12个肝脏样本，构建了包含EAD发生和EAD未发生的人移植肝单细胞转录组图谱。通过分析EAD发生和EAD未发生患者的75 231个单细胞，发现了一种与 EAD发生显著相关的由黏膜相关不变 T 细胞（(mucosal associated invariant T cell, MAIT）、颗粒酶B+（GZMB+）和颗粒酶K+（GZMK+）自然杀伤细胞以及S100钙结合蛋白A12+ （S100A12）中性粒细胞组成的免疫生态位。此外，在两个独立队列中也进一步验证了这种免疫生态位的存在及其与EAD 发生的相关性。综上，本文研究结果在单细胞水平上揭示了移植肝的细胞特征以及一种与EAD发生相关的致病免疫生态位，为理解EAD发生发展机制提供了新的见解。

Abstract

Liver transplantation (LT) is the standard therapy for individuals afflicted with end-stage liver disease. Despite notable advancements in LT technology, the incidence of early allograft dysfunction (EAD) remains a critical concern, exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients. Unfortunately, the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD. Herein, we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients, with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages. Comparison of the 75 231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells, granzyme B+ (GZMB +) granzyme K+ (GZMK +) natural killer cells, and S100 calcium binding protein A12+ (S100A12 +) neutrophils. Moreover, we verified this immune niche and its association with EAD occurrence in two independent cohorts. Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level, thus, offering valuable insights into EAD onset.

关键词

人类肝移植 / 早期移植物功能不全 / 致病免疫生态位 / 单细胞分析 / 细胞间通讯

Keywords

Human liver transplantation / Early allograft dysfunction / Pathogenic immune niche / Single-cell analysis / Cell-cell communication

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Xin Shao, Zheng Wang, Kai Wang. 人类肝移植图谱揭示了一种与早期移植物功能不全发生相关的致病免疫生态位. Engineering. 2024, 36(5): 193-208 https://doi.org/10.1016/j.eng.2023.12.004

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