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Visium spatial transcriptomics and proteomics identifies novel hepatic cell populations and transcriptomic signatures of alcohol-associated hepatitis

ABSTRACT: Background: Alcohol-associated hepatitis (AH) is the clinical manifestation of alcohol-associated liver disease (ALD). AH is a complex disease encompassing the dysregulation of many cells and cell subpopulations. This study used a hepatic spatial transcriptomic and proteomic approach (10X Genomics Visium) to identify hepatic cell populations and their associated transcriptomic and proteomic alterations in human AH. Methods: Formalin fixed parraffin embedded liver tissue from AH patients (n=2) and non-ALD controls (donors) (n=2) were used for Visium spatial transcriptomic and proteomic analysis. Results: AH cell clusters and cell markers were drastically different in regard to tissue pattern and number of cell type as compared to non-ALD controls. Cholangiocytes, endothelial cells, macrophages, and stellate cells were more profuse in AH relative to non-ALD controls. Transcriptionally, proliferating cell nuclear antigen positive (PCNA+) hepatocytes in AH more closely resembled cholangiocytes suggesting they were non-functional hepatocytes derived from cholangiocytes. Further, mitochondria protein coding genes were reduced in AH vs non-ALD control hepatocytes, suggesting reduced functionality and loss of regenerative mechanisms. Macrophages in AH exhibited elevated gene expression involved in exosomes as compared to non-ALD controls. The most upregulated macrophage genes observed in AH were those involved in exosome trafficking and cellular migration. Gene and protein signatures of disease associated hepatocytes (ANXA2+/CXCL1+/CEACAM8+) were elevated in AH and could visually identify a pre-malignant lesion. Conclusions: This study identified global cell type alterations in AH and distinct transcriptomic changes between AH and non-ALD controls. These findings characterizes cellular plasticity and profuse transcriptomic and proteomic changes that are apparent in AH and contributes to the identification of novel therapeutics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE278662 | GEO | 2024/12/02

REPOSITORIES: GEO

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Project description:Background & aims: The role of microRNAs (miRNAs) in Alcoholic Hepatitis (AH) and their potential as therapeutic targets in liver disease has not been explored yet. This study aims at profiling miRNA in AH and identifying dysregulated miRNAs involved in AH pathophysiology. Methods: miRNA expression arrays were performed in 13 AH, 5 alcohol liver disease-induced cirrhosis (ALD-CH), 5 nonalcoholic steatohepatitis induced cirrhosis (NASH-CH), 4 HCV-induced cirrhosis (HCV-CH) and 6 non-injured liver control samples. Genome wide expression profile was retrieved for 12 paired AH and control samples. MiRNA and mRNA expression data was integrated and identified miRNAs were validated in AH samples and in animal models of liver injury. Results:Â The miRNA array showed 111 upregulated and 66 downregulated miRNAs in AH versus healthy subjects. The comparison of miRNA profile in liver samples from AH among ALD-CH, HCV-CH and NASH-CH identified 18 miRNAs specifically dysregulated in AH. Integrative miRNA and mRNA analysis in AH identified dysregulated miRNAs for which their target genes were also dysregulated. A functional analysis of identified miRNAs and their targets revealed their involvement in the regulation of canonical pathways related to apoptosis, fatty acid metabolism and cell cycle among others. miRNAs expression (miR-182, miR-21, miR-155, miR-214, miR-432, miR-422a) was validated in an independent cohort of AH. MiR-182 expression correlated with cholestasis, disease severity and short-term mortality. Moreover, miR-182 expression is associated to cholestasis with ductular reaction but not to fibrosis and inflammation in animal models of liver injury. Conclusions:Â AH is characterized by an important dysregulation of miRNA expression with a unique miRNA profile. MiRNAs specifically expressed in AH are associated to cholestasisâ¦ Uncovered miRNAs are involved in important pathophysiological features in AH suggesting ta regulation of he role of miRNAs in the regulation of AH, and highlight miR-182 as a potential regulator of its pathophysiology. miRNA expression arrays were performed in 13 AH(Alcoholic hepatitis), 5 alcohol liver disease-induced cirrhosis (ALD-CH), 5 nonalcoholic steatohepatitis induced cirrhosis (NASH-CH), 4 HCV-induced cirrhosis (HCV-CH) and 6 non-injured liver control samples(CTRL).

Project description:Background & aims: The role of microRNAs (miRNAs) in Alcoholic Hepatitis (AH) and their potential as therapeutic targets in liver disease has not been explored yet. This study aims at profiling miRNA in AH and identifying dysregulated miRNAs involved in AH pathophysiology. Methods: miRNA expression arrays were performed in 13 AH, 5 alcohol liver disease-induced cirrhosis (ALD-CH), 5 nonalcoholic steatohepatitis induced cirrhosis (NASH-CH), 4 HCV-induced cirrhosis (HCV-CH) and 6 non-injured liver control samples. Genome wide expression profile was retrieved for 12 paired AH and control samples. MiRNA and mRNA expression data was integrated and identified miRNAs were validated in AH samples and in animal models of liver injury. Results: The miRNA array showed 111 upregulated and 66 downregulated miRNAs in AH versus healthy subjects. The comparison of miRNA profile in liver samples from AH among ALD-CH, HCV-CH and NASH-CH identified 18 miRNAs specifically dysregulated in AH. Integrative miRNA and mRNA analysis in AH identified dysregulated miRNAs for which their target genes were also dysregulated. A functional analysis of identified miRNAs and their targets revealed their involvement in the regulation of canonical pathways related to apoptosis, fatty acid metabolism and cell cycle among others. miRNAs expression (miR-182, miR-21, miR-155, miR-214, miR-432, miR-422a) was validated in an independent cohort of AH. MiR-182 expression correlated with cholestasis, disease severity and short-term mortality. Moreover, miR-182 expression is associated to cholestasis with ductular reaction but not to fibrosis and inflammation in animal models of liver injury. Conclusions: AH is characterized by an important dysregulation of miRNA expression with a unique miRNA profile. MiRNAs specifically expressed in AH are associated to cholestasis… Uncovered miRNAs are involved in important pathophysiological features in AH suggesting ta regulation of he role of miRNAs in the regulation of AH, and highlight miR-182 as a potential regulator of its pathophysiology.

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Visium spatial transcriptomics and proteomics identifies novel hepatic cell populations and transcriptomic signatures of alcohol-associated hepatitis

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