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RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.

ABSTRACT: Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In this study, we aimed to characterise human HPCs and their interactions with other cells through comparison, on both protein and RNA level, of HPC-enriched cell populations from adult human liver tissue using different isolation methods. Fresh human liver tissue was collected from ASH explant livers and HPC-enriched cell populations were obtained via four different isolation methods: side population (SP), epithelial cell adhesion molecule (EpCAM) and trophoblast antigen 2 (TROP-2) membrane marker isolation and laser capture microdissection. Gene expression profiles of fluorescent-activated cell-sorted HPCs, whole liver extracts and laser microdissected HPC niches were determined by RNA-sequencing. Immunohistochemical evaluation of the isolated populations indicated the enrichment of HPCs in the SP, EpCAM+ and TROP-2+ cell populations. Pathway analysis of the transcription profiles of human HPCs showed an enrichment and activation of known HPC pathways like Wnt/?-catenin, TWEAK and HGF. Integration of the HPC niche profile suggests autocrine signalling by HPCs (TNF?, PDGFB and VEGFA) as well as paracrine signalling from the surrounding niche cells including MIF and IGF-1. In addition, we identified IL-17?A signalling as a potentially novel pathway in HPC biology. In conclusion, we provide the first RNA-seq-based, comparative transcriptome analysis of isolated human HPCs from ASH patients and revealed active signalling between HPCs and their surrounding niche cells in ASH livers and suggest that HPCs can actively contribute to liver inflammation.

SUBMITTER: Ceulemans A

PROVIDER: S-EPMC5775409 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.

Ceulemans An A Verhulst Stefaan S Van Haele Matthias M Govaere Olivier O Ventura Juan-Jose JJ van Grunsven Leo A LA Roskams Tania T

Cell death & disease 20171102 11

Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In t ...[more]

PMID: 29095436

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Project description:BackgroundNon-alcoholic fatty liver disease is the most common liver disease globally and in its inflammatory form, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continued progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and hepatocyte apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that liver progenitor cells (LPCs) response plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH.MethodsExperimental NASH was induced in C57BL/6 J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 106 hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured.ResultshAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNβ in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation.ConclusionsExpansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation.

Project description:This paper is based upon the "Charles Lieber Satellite Symposia" organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human immunodeficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Dataset Information

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.

Publications

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers.

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