小柯机器人

科学家揭示肝硬化细胞水平发病机制
2019-10-10 13:09

英国爱丁堡大学炎症研究中心N. C. Henderson和P. Ramachandran研究组合作发现在单细胞水平上肝硬化的纤维化生态位。相关论文2019年10月9日在线发表于《自然》。

为了获得细胞水平的直接相关的发病机制,并为治疗设计提供依据,他们分析了超过100,000个人类单细胞的转录组,从而得出了健康和肝硬化人类肝脏中存在的非实质细胞类型的分子定义。他们发现了一种新型的与疤痕相关的TREM2+CD9+巨噬细胞亚群,该亚群在肝纤维化中扩展,从循环单核细胞分化,并且具有促纤维化作用。他们还定义了新型ACKR1+和PLVAP+内皮细胞,它们在肝硬化中扩展,在形态构造上受疤痕限制并增强白细胞的转运。新型疤痕相关巨噬细胞,内皮细胞与PDGFRα+胶原生成间充质细胞之间相互作用的多谱系配体-受体模型揭示了包括TNFRSF12A,PDGFR和NOTCH信号传导在内的几种促纤维化途径的疤痕内活性。

他们的工作在单细胞水平上剖析了未曾被预料的人体器官纤维化的细胞和分子基础,并提供了发现肝硬化合理治疗目标所需的概念框架。

据悉,目前尚无有效的抗肝纤维化疗法治疗肝硬化,肝硬化是全世界的主要杀手。

附:英文原文

Title: Resolving the fibrotic niche of human liver cirrhosis at single-cell level

Author: P. Ramachandran, R. Dobie, J. R. Wilson-Kanamori, E. F. Dora, B. E. P. Henderson, N. T. Luu, J. R. Portman, K. P. Matchett, M. Brice, J. A. Marwick, R. S. Taylor, M. Efremova, R. Vento-Tormo, N. O. Carragher, T. J. Kendall, J. A. Fallowfield, E. M. Harrison, D. J. Mole, S. J. Wigmore, P. N. Newsome, C. J. Weston, J. P. Iredale, F. Tacke, J. W. Pollard, C. P. Ponting, J. C. Marioni, S. A. Teichmann, N. C. Henderson

Issue&Volume: 2019-10-09

Abstract: 

Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 human single cells, yielding molecular definitions for non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2+CD9+ macrophage subpopulation, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define novel ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically scar-restricted and enhance leucocyte transmigration. Multi-lineage ligand-receptor modelling of interactions between the novel scar-associated macrophages, endothelial cells and PDGFRα+ 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 the conceptual framework required to discover rational therapeutic targets in liver cirrhosis.

DOI: 10.1038/s41586-019-1631-3

Source:https://www.nature.com/articles/s41586-019-1631-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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