Resolving the fibrotic niche of human liver cirrhosis at single-cell level
Resolving the fibrotic niche of human liver cirrhosis at single-cell level
复制标题
DOI：
10.1038/s41586-019-1631-3
复制
发表时间：
2019-11-21
期刊：
影响因子：
64.8
通讯作者：
Henderson, N. C.
中科院分区：
文献类型：
--
作者：
Ramachandran, P.;Dobie, R.;Henderson, N. C.
肝硬变是世界范围内死亡的主要原因，其特点是广泛的纤维化。目前还没有有效的抗纤维化治疗方法可用。为了更好地了解疾病发病机制中涉及的细胞和分子机制，并能够发现治疗靶点，这里我们分析了100,000多个单个人类细胞的转录本，得出了在健康和肝硬变的人类肝脏中发现的非实质细胞类型的分子定义。我们确定了与瘢痕相关的TREM2(+)CD9(+)巨噬细胞亚群，它在肝纤维化中扩张，与循环单核细胞不同，是促纤维化的。我们还定义了ACKR1(+)和PLVAP(+)内皮细胞在肝硬变中扩张，在地形图上局限于纤维化的壁龛，并增强白细胞的迁移。对瘢痕相关巨噬细胞、内皮细胞和PDGFRα(+)胶原生成间充质细胞之间的配体和受体相互作用的多谱系模型揭示了几种促纤维化通路的瘢痕内活性，包括TNFRSF12A、PDGFR和Notch信号。我们的工作在单细胞水平上剖析了人类器官纤维化的细胞和分子基础的意想不到的方面，并为发现肝硬变的合理治疗靶点提供了一个概念性框架。
Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2(+)CD9(+) subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1(+) and PLVAP(+) endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFR alpha(+) collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.