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Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. ​

文献信息 ​

DOI10.1038/s41590-018-0276-y
PMID30643263
期刊Nature immunology
影响因子27.6
JCR 分区Q1
发表年份2019
被引次数2393
关键词单细胞RNA测序, 肺纤维化, 转型巨噬细胞, 病理亚群, CX3CR1+SiglecF+
文献类型Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN1529-2908
页码163-172
期号20(2)
作者Dvir Aran, Agnieszka P Looney, Leqian Liu, Esther Wu, Valerie Fong, Austin Hsu, Suzanna Chak, Ram P Naikawadi, Paul J Wolters, Adam R Abate, Atul J Butte, Mallar Bhattacharya

一句话小结 ​

本研究通过单细胞RNA测序揭示了小鼠博来霉素诱导的肺纤维化中巨噬细胞的异质性，特别识别出一种CX3CR1+SiglecF+过渡巨噬细胞亚群，该亚群在纤维化微环境中具有促纤维化作用，并且其基因表达在人类特发性肺纤维化患者中也显著上调。这一发现为理解巨噬细胞在纤维化过程中的角色提供了新的视角，并可能为靶向治疗纤维化相关疾病开辟新的方向。

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单细胞RNA测序 · 肺纤维化 · 转型巨噬细胞 · 病理亚群 · CX3CR1+SiglecF+

摘要 ​

组织纤维化是由活化的间充质细胞沉积基质蛋白引起的主要死亡原因。巨噬细胞在纤维化过程中积聚，但特定亚群在支持纤维生成中的作用尚未在体内研究。本文使用单细胞RNA测序（scRNA-seq）对小鼠博来霉素诱导的肺纤维化中的巨噬细胞异质性进行了表征。通过参考总体转录组的单细胞RNA测序注释的新计算框架（SingleR）使巨噬细胞的亚集群化成为可能，并揭示了一个与疾病相关的亚群，其基因表达谱在单核细胞来源和肺泡巨噬细胞之间呈过渡状态。这些CX3CR1+SiglecF+过渡巨噬细胞定位于纤维化微环境中，并在体内具有促纤维化的作用。过渡巨噬细胞表达的基因在人类特发性肺纤维化患者的样本中上调。因此，我们已确定了一种病理性过渡巨噬细胞亚群，这些细胞在对损伤的纤维化反应中是必需的。

英文摘要 ​

Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.

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主要研究问题 ​

  1. 这种过渡性巨噬细胞在肺纤维化的不同阶段中是否表现出不同的基因表达特征？
  2. 在其他类型的纤维化疾病中，是否也能观察到类似的过渡性巨噬细胞亚群？
  3. 针对这种过渡性巨噬细胞的治疗策略是否已经在临床试验中进行评估？
  4. 这种巨噬细胞亚群的识别是否可以用于早期诊断肺纤维化患者的风险？
  5. 是否有其他的单细胞测序技术可以进一步验证这些发现，并探讨巨噬细胞的功能？

核心洞察 ​

研究背景和目的 ​

肺纤维化是一种导致高死亡率的疾病，特征为基质蛋白的沉积。尽管巨噬细胞在纤维化过程中积累，但特定亚群在支持纤维化中的作用尚未得到充分研究。本研究旨在利用单细胞RNA测序（scRNA-seq）技术，深入探讨在小鼠的博来霉素诱导肺纤维化模型中，巨噬细胞的异质性及其在纤维化中的功能。

主要方法/材料/实验设计 ​

本研究采用了以下方法：

  1. 单细胞RNA测序（scRNA-seq）：使用博来霉素处理小鼠，诱导肺纤维化，随后进行肺组织的单细胞分离和RNA测序。
  2. SingleR算法：开发了一种计算工具SingleR，通过与参考数据集比较，进行细胞类型的无偏注释和聚类分析。
  3. 功能实验：通过细胞培养和小鼠模型，评估巨噬细胞对成纤维细胞增殖和迁移的影响。

以下是研究的技术路线流程图（Mermaid代码）：

Mermaid diagram

关键结果和发现 ​

  1. 巨噬细胞亚群：通过SingleR分析，识别出肺巨噬细胞的三种亚群：C1（肺泡巨噬细胞）、C2（过渡巨噬细胞）和C3（间质巨噬细胞）。C2亚群表现出介于C1和C3之间的基因表达特征，且在纤维化部位富集。
  2. 功能验证：特异性去除C2亚群巨噬细胞显著减少了肺纤维化的发生，表明C2巨噬细胞在纤维化反应中发挥了重要作用。
  3. PDGF-AA的作用：C2巨噬细胞是PDGF-AA的主要来源，PDGF-AA通过促进成纤维细胞的增殖，促进了纤维化的进程。

主要结论/意义/创新性 ​

本研究首次识别出在肺纤维化过程中起关键作用的过渡巨噬细胞亚群，提供了对巨噬细胞与成纤维细胞相互作用的新视角。这一发现可能为开发针对肺纤维化的新疗法提供了潜在靶点，如针对PDGF信号通路的干预。

研究局限性和未来方向 ​

  1. 局限性：Cx3cr1在C2和C3两种巨噬细胞中均有表达，限制了研究的特异性。此外，SingleR算法的注释依赖于参考数据集的质量。
  2. 未来方向：建议进一步研究C2和C3巨噬细胞的转化动态，并探索针对特定巨噬细胞亚群的治疗策略，以期改善肺纤维化患者的预后。

参考文献 ​

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引用本文的文献 ​

  1. Defining the Cell Types That Drive Idiopathic Pulmonary Fibrosis Using Single-Cell RNA Sequencing. - Joanna M Poczobutt;Oliver Eickelberg - American journal of respiratory and critical care medicine (2019)
  2. Single-Cell Profiling of Cutaneous T-Cell Lymphoma Reveals Underlying Heterogeneity Associated with Disease Progression. - Nicholas Borcherding;Andrew P Voigt;Vincent Liu;Brian K Link;Weizhou Zhang;Ali Jabbari - Clinical cancer research : an official journal of the American Association for Cancer Research (2019)
  3. Dissecting Cellular Heterogeneity Using Single-Cell RNA Sequencing. - Yoon Ha Choi;Jong Kyoung Kim - Molecules and cells (2019)
  4. Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease. - Jia Fu;Kemal M Akat;Zeguo Sun;Weijia Zhang;Detlef Schlondorff;Zhihong Liu;Thomas Tuschl;Kyung Lee;John Cijiang He - Journal of the American Society of Nephrology : JASN (2019)
  5. Epithelial Expression of an Interstitial Lung Disease-Associated Mutation in Surfactant Protein-C Modulates Recruitment and Activation of Key Myeloid Cell Populations in Mice. - Alessandro Venosa;Jeremy Katzen;Yaniv Tomer;Meghan Kopp;Sarita Jamil;Scott J Russo;Surafel Mulugeta;Michael F Beers - Journal of immunology (Baltimore, Md. : 1950) (2019)
  6. The immunopathology of lung fibrosis: amphiregulin-producing pathogenic memory T helper-2 cells control the airway fibrotic responses by inducing eosinophils to secrete osteopontin. - Kiyoshi Hirahara;Ami Aoki;Yuki Morimoto;Masahiro Kiuchi;Mikiko Okano;Toshinori Nakayama - Seminars in immunopathology (2019)
  7. scMatch: a single-cell gene expression profile annotation tool using reference datasets. - Rui Hou;Elena Denisenko;Alistair R R Forrest - Bioinformatics (Oxford, England) (2019)
  8. Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer. - Giuseppe Sammarco;Gilda Varricchi;Valentina Ferraro;Michele Ammendola;Michele De Fazio;Donato Francesco Altomare;Maria Luposella;Lorenza Maltese;Giuseppe Currò;Gianni Marone;Girolamo Ranieri;Riccardo Memeo - International journal of molecular sciences (2019)
  9. The role of macrophages in the resolution of inflammation. - Satoshi Watanabe;Michael Alexander;Alexander V Misharin;G R Scott Budinger - The Journal of clinical investigation (2019)
  10. Dissecting lung development and fibrosis at single-cell resolution. - Donna L Farber;Peter A Sims - Genome medicine (2019)

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