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

Abstract

	•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.、

Keywords

ALB ⁺KRT7 ⁺ epithelium / alcohol-related liver disease / single-cell RNA-seq / Wnt/β-catenin

References

[1] Mackowiak B, Fu Y, Maccioni L, et al. Alcohol-associated liver disease. J Clin Invest. 2024;134.

[2] Moon AM, Singal AG, Tapper EB. Contemporary epidemiology of chronic liver disease and cirrhosis. Clin Gastroenterol Hepatol. 2020;18:2650-2666.

[3] Pimpin L, Cortez-Pinto H, Negro F, et al. Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies. J Hepatol. 2018;69:718-735.

[4] Seitz HK, Bataller R, Cortez-Pinto H, et al. Alcoholic liver disease. Nat Rev Dis Primers. 2018;4:16.

[5] Zhang FY, Gao YH. [Immune cells role and their new potential therapeutic targets in the pathogenesis of alcoholic liver disease]. Zhonghua Gan Zang Bing Za Zhi. 2021;29:510-514.

[6] Ganne-Carrie N, Nahon P. Hepatocellular carcinoma in the setting of alcohol-related liver disease. J Hepatol. 2019;70:284-293.

[7] Jeon S, Carr R. Alcohol effects on hepatic lipid metabolism. J Lipid Res. 2020;61:470-479.

[8] Lackner C, Tiniakos D. Fibrosis and alcohol-related liver disease. J Hepatol. 2019;70:294-304.

[9] Kim A, Wu X, Allende DS, et al. Gene deconvolution reveals aberrant liver regeneration and immune cell infiltration in alcohol-associated hepatitis. Hepatology. 2021;74:987-1002.

[10] Cao L, Wu D, Qin L, et al. Single-cell RNA transcriptome profiling of liver cells of short-term alcoholic liver injury in mice. Int J Mol Sci. 2023;24.

[11] Guan Y, Peiffer B, Feng D, et al. IL-8+ neutrophils drive inexorable inflammation in severe alcohol-associated hepatitis. J Clin Invest. 2024;134.

[12] Pawella LM, Hashani M, Eiteneuer E, et al. Perilipin discerns chronic from acute hepatocellular steatosis. J Hepatol. 2014;60:633-642.

[13] Aguilar-Bravo B, Arino S, Blaya D, et al. Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming. bioRxiv. 2023.

[14] Li L, Cui L, Lin P, et al. Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers. Cell Stem Cell. 2023;30:283-299.

[15] Lukacs-Kornek V, Lammert F. The progenitor cell dilemma: cellular and functional heterogeneity in assistance or escalation of liver injury. J Hepatol. 2017;66:619-630.

[16] Gadd VL, Aleksieva N, Forbes SJ. Epithelial plasticity during liver injury and regeneration. Cell Stem Cell. 2020;27:557-573.

[17] Cardinale V, Wang Y, Carpino G, et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology. 2011;54:2159-2172.

[18] Zhang H, Siegel CT, Shuai L, et al. Repair of liver mediated by adult mouse liver neuro-glia antigen 2-positive progenitor cell transplantation in a mouse model of cirrhosis. Sci Rep. 2016;6:21783.

[19] Qiu Q, Hernandez JC, Dean AM, et al. CD24-positive cells from normal adult mouse liver are hepatocyte progenitor cells. Stem Cells Dev. 2011;20:2177-2188.

[20] La Manno G, Soldatov R, Zeisel A, et al. RNA velocity of single cells. Nature. 2018;560:494-498.

[21] Yu B, He ZY, You P, et al. Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. Cell Stem Cell. 2013;13:328-340.

[22] Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. 2019;575:512-518.

[23] Zhang Y, Fan Y, He W, et al. Persistent deficiency of mucosa-associated invariant T (MAIT) cells during alcohol-related liver disease. Cell Biosci. 2021;11:148.

[24] Riva A, Patel V, Kurioka A, et al. Mucosa-associated invariant T cells link intestinal immunity with antibacterial immune defects in alcoholic liver disease. Gut. 2018;67:918-930.

[25] Wu H, Zhou X, Fu GB, et al. Reversible transition between hepatocytes and liver progenitors for in vitro hepatocyte expansion. Cell Res. 2017;27:709-712.

[26] Li X, Li Y, Xiao J, et al. Unique DUOX2(+)ACE2(+) small cholangiocytes are pathogenic targets for primary biliary cholangitis. Nat Commun. 2023;14:29.

[27] Su T, Yang Y, Lai S, et al. Single-cell transcriptomics reveals zone-specific alterations of liver sinusoidal endothelial cells in cirrhosis. Cell Mol Gastroenterol Hepatol. 2021;11:1139-1161.

[28] Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021;18:40-55.

[29] Stueck AE, Wanless IR. Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis. Hepatology. 2015;61:1696-1707.

[30] Sackett SD, Li Z, Hurtt R, et al. Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology. 2009;49:920-929.

[31] Pu W, Zhu H, Zhang M, et al. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat Genet. 2023;55:651-664.

[32] Gribben C, Galanakis V, Calderwood A, et al. Acquisition of epithelial plasticity in human chronic liver disease. Nature. 2024;630:166-173.

[33] Huch M, Gehart H, van Boxtel R, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell. 2015;160:299-312.

[34] Okabe H, Yang J, Sylakowski K, et al. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology. 2016;64:1652-1666.

[35] Wilson DH, Jarman EJ, Mellin RP, et al. Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors. Nat Commun. 2020;11:445.

[36] Pepe-Mooney BJ, Dill MT, Alemany A, et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell. 2019;25:23-38.

[37] Huang X, Zhu H, Gao Z, et al. Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p. J Biol Chem. 2018;293:6693-6706.

[38] King ML, Lindberg ME, Stodden GR, et al. WNT7A/beta-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene. 2015;34:3452-3462.

[39] Zhang Y, Xu H, Cui G, et al. beta-catenin sustains and is required for YES-associated protein oncogenic activity in cholangiocarcinoma. Gastroenterology. 2022;163:481-494.

[40] Yin C, Evason KJ, Asahina K, et al. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest. 2013;123:1902-1910.

[41] Ishikawa T, Factor VM, Marquardt JU, et al. Hepatocyte growth factor/c-met signaling is required for stem-cell-mediated liver regeneration in mice. Hepatology. 2012;55:1215-1226.

[42] Yang D, Li Q, Shang R, et al. WNT4 secreted by tumor tissues promotes tumor progression in colorectal cancer by activation of the Wnt/beta-catenin signalling pathway. J Exp Clin Cancer Res. 2020;39:251.

[43] Halpern KB, Shenhav R, Massalha H, et al. Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells. Nat Biotechnol. 2018;36:962-970.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.