Single-cell landscape of the intrahepatic ecosystem in alcohol-related liver disease

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Clinical and Translational Medicine Pub Date : 2025-01-20 DOI:10.1002/ctm2.70198

Xiaofang Zhao, Senyan Wang, Qi Liu, Wenjuan Wei, Xiaoyan Sun, Hao Song, Jing Xu, Shuijun Zhang, Hongyang Wang, Jing Fu

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Abstract

Alcohol-related liver disease (ALD) is a common chronic liver disease caused by long-term excessive alcohol consumption and responsible for more than half of all liver-related deaths worldwide. The molecular mechanisms associated with ALD were not fully understood. In this study, we performed single-cell RNA sequencing on liver tissues obtained from ALD patients and healthy liver donors. We identified an ALB⁺KRT7⁺ epithelial population that expressed both hepatocyte and biliary markers significantly expanded in ALD livers. The ALB⁺KRT7⁺ epithelial cells were demonstrated to have stem cell properties and malignant transformation potentials. Moreover, ALB⁺KRT7⁺ epithelium-derived ALD organoids promote the tumour growth by activating Wnt/β-catenin signalling of liver cancer cells. Most importantly, blocking the Wnt protein secretion or knockdown the Wnt receptor suppressed the tumour promoting effect of ALD organoids. Our study provides important insights that Wnt signalling can be targeted in patients with advanced alcohol-related cirrhosis to prevent malignant transformation. In addition, our results also uncovered the important alterations of nonparenchymal cells, especially macrophages and T/NK populations that responsible for active inflammation responses in alcohol-related hepatitis and immunosuppressive microenvironment in advanced cirrhosis livers, which likely facilitated the malignant progression of ALD.

Key points

This study provides single-cell landscape of human liver samples across different ALD stages.
The ALB⁺ KRT7⁺ epithelium were enriched in ALD patients, and the function of this epithelial population varied significantly across ALD stages.
ALB⁺KRT7⁺ epithelium from advanced alcohol-related cirrhosis had malignant transformation potential and tumour promotion activity.
The comprehensive changes of parenchymal and nonparenchymal cells in the ALD livers lay a hidden danger for the further malignant progression.

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酒精相关性肝病中肝内生态系统的单细胞景观

酒精相关性肝病（ALD）是一种由长期过量饮酒引起的常见慢性肝病，在全世界与肝脏相关的死亡中占一半以上。与ALD相关的分子机制尚不完全清楚。在这项研究中，我们对ALD患者和健康肝脏供者的肝组织进行了单细胞RNA测序。我们发现ALB+KRT7+上皮细胞群在ALD肝脏中表达肝细胞和胆道标志物显著扩增。结果表明，ALB+KRT7+上皮细胞具有干细胞特性和恶性转化潜能。此外，ALB+KRT7+上皮来源的ALD类器官通过激活肝癌细胞的Wnt/β-catenin信号传导促进肿瘤生长。最重要的是，阻断Wnt蛋白分泌或敲低Wnt受体可抑制ALD类器官的促肿瘤作用。我们的研究提供了重要的见解，即Wnt信号可以靶向晚期酒精相关性肝硬化患者以预防恶性转化。此外，我们的研究结果还揭示了非实质细胞，特别是巨噬细胞和T/NK细胞群的重要改变，这些细胞在酒精相关性肝炎和晚期肝硬化的免疫抑制微环境中负责活跃的炎症反应，这可能促进了ALD的恶性进展。本研究提供了不同ALD阶段人类肝脏样本的单细胞图谱。ALB+ KRT7+上皮在ALD患者中富集，并且该上皮群的功能在ALD的不同阶段有显著差异。晚期酒精相关性肝硬化的ALB+KRT7+上皮具有恶性转化潜能和肿瘤促进活性。ALD肝实质细胞和非实质细胞的全面改变为进一步恶性进展埋下了隐患。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.