The dynamic cellular landscape of grafts with acute rejection after heart transplantation
The dynamic cellular landscape of grafts with acute rejection after heart transplantation
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心脏移植后急性排斥反应的移植物的动态细胞景观
DOI：
10.1016/j.healun.2022.10.017
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发表时间：
2023-01-12
影响因子：
8.9
通讯作者：
Gong, Weihua
中科院分区：
文献类型：
--
作者：
Kong, Deqiang;Huang, Siyuan;Gong, Weihua
背景：急性细胞排斥反应(ACR)是心脏移植物长期存活的主要障碍。虽然免疫细胞在ACR中起着关键作用，但ACR同种异体心脏移植物的动态细胞格局仍不清楚。方法：对ACR小鼠同种异体心脏移植物进行单细胞RNA测序。结果：尽管心脏成纤维细胞(CFB)总体上大量耗尽，但在移植的晚期，高度扩增的细胞毒性T淋巴细胞和CXCL10+GBP2+CFB亚群得到了丰富。CXCL10+GBP2+CFB具有较强的干扰素反应性，高表达趋化因子和主要组织相容性复合体分子，提示其参与免疫细胞的募集和激活。细胞间通讯分析表明，CXCL9/CXCL10-CXCR3可能参与调控CXCL10+GBP2+CFB诱导的趋化和免疫细胞募集。体内移植研究揭示了CXCR3拮抗剂在移植排斥反应中的治疗潜力。结论：我们的研究结果揭示了一个可能介导急性心脏排斥反应的新的CFB亚群。靶向CXCR3可延长同种异体移植物存活时间.心肺移植杂志2023；42：160-172
BACKGROUND: Acute cellular rejection (ACR) is a major barrier to the long-term survival of cardiac allografts. Although immune cells are well known to play critical roles in ACR, the dynamic cellular landscape of allografts with ACR remains obscure.METHODS: Single-cell RNA sequencing (scRNA-seq) was carried out for mouse cardiac allografts with ACR. Bioinformatic analysis was performed, and subsequent transplant experiments were conducted to validate the findings.RESULTS: Despite an overall large depletion of cardiac fibroblasts (CFBs), highly expanded cytotoxic T lymphocytes and a CXCL10+Gbp2+ subcluster of CFBs were enriched within grafts at the late stage. CXCL10+Gbp2+ CFBs featured strong interferon responsiveness and high expression of chemokines and major histocompatibility complex molecules, implying their involvement in the recruitment and acti-vation of immune cells. Cell-cell communication analysis revealed that CXCL9/CXCL10-CXCR3 might contribute to regulating CXCL10+Gbp2+ CFB-induced chemotaxis and immune cell recruitment. In vivo transplant studies revealed the therapeutic potential of CXCR3 antagonism in transplant rejection.CONCLUSIONS: The findings of our study unveiled a novel CFB subcluster that might mediate acute cardiac rejection. Targeting CXCR3 could prolong allograft survival.J Heart Lung Transplant 2023;42:160-172