Single-cell RNA sequencing of subcutaneous adipose tissues identifies therapeutic targets for cancer-associated lymphedema.
Single-cell RNA sequencing of subcutaneous adipose tissues identifies therapeutic targets for cancer-associated lymphedema.
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皮下脂肪组织的单细胞 RNA 测序确定了癌症相关淋巴水肿的治疗靶点
DOI：
10.1038/s41421-022-00402-5
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发表时间：
2022-06-21
期刊：
影响因子：
33.5
通讯作者：
Long, Xiao
中科院分区：
文献类型：
--
作者：
Liu, Xuanyu;Yuan, Meng;Xiang, Qinqin;Li, Zhujun;Xu, Fen;Chen, Wen;Chen, Jie;Huang, Jiuzuo;Yu, Nanze;Zhou, Zhou;Long, Xiao
癌症相关淋巴水肿常常发生在为治疗癌症而进行的淋巴切除术后。然而，我们仍然缺乏有效的有针对性的药物治疗或预防这种并发症。深入阐明淋巴水肿皮下脂肪组织的细胞变化对于医学发展是至关重要的。我们对70,209个来自淋巴水肿患者和健康捐赠者的脂肪组织间质血管部分的细胞进行了单细胞RNA测序。鉴定了脂肪基质细胞(ASCs)的四个亚群。其中，PRG4+/CLEC3B+ASC亚群c3在淋巴水肿时显著扩大，并与脂肪组织纤维化有关。体外敲除CLEC3B基因可显著减轻患者ASCs的纤维化形成。淋巴水肿的脂肪组织显示Lyve+抗炎巨噬细胞显著减少，并表现出促炎的微环境。用十二肽小鼠LR12药理阻断Trem1，一种主要由促炎巨噬细胞表达的免疫受体，可以显著减轻小鼠尾巴模型中的淋巴水肿。细胞-细胞通讯分析揭示了血管干细胞、巨噬细胞和血管内皮细胞之间的血管周围配体-受体相互作用模块。我们在单细胞分辨率下对淋巴水肿患者脂肪组织的谱系特异性变化进行了全面的分析。CLEC3B被发现是缓解脂肪组织纤维化的潜在靶点。用LR12药物阻断TREM1可以作为治疗淋巴水肿的一种有前途的药物。
Cancer-associated lymphedema frequently occurs following lymph node resection for cancer treatment. However, we still lack effective targeted medical therapies for the treatment or prevention of this complication. An in-depth elucidation of the cellular alterations in subcutaneous adipose tissues of lymphedema is essential for medical development. We performed single-cell RNA sequencing of 70,209 cells of the stromal vascular fraction of adipose tissues from lymphedema patients and healthy donors. Four subpopulations of adipose-derived stromal cells (ASCs) were identified. Among them, the PRG4+/CLEC3B+ ASC subpopulation c3 was significantly expanded in lymphedema and related to adipose tissue fibrosis. Knockdown of CLEC3B in vitro could significantly attenuate the fibrogenesis of ASCs from patients. Adipose tissues of lymphedema displayed a striking depletion of LYVE+ anti-inflammatory macrophages and exhibited a pro-inflammatory microenvironment. Pharmacological blockage of Trem1, an immune receptor predominantly expressed by the pro-inflammatory macrophages, using murine LR12, a dodecapeptide, could significantly alleviate lymphedema in a mouse tail model. Cell–cell communication analysis uncovered a perivascular ligand-receptor interaction module among ASCs, macrophages, and vascular endothelial cells. We provided a comprehensive analysis of the lineage–specific changes in the adipose tissues from lymphedema patients at a single-cell resolution. CLEC3B was found to be a potential target for alleviating adipose tissue fibrosis. Pharmacological blockage of TREM1 using LR12 could serve as a promising medical therapy for treating lymphedema.
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影响因子：
3.7
作者：
Jablonski KA;Amici SA;Webb LM;Ruiz-Rosado Jde D;Popovich PG;Partida-Sanchez S;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
51.1
作者：
DiSipio, Tracey;Rye, Sheree;Hayes, Sandi
通讯作者：
Hayes, Sandi
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser