Liver transcriptome analysis reveals PSC-attributed gene set associated with fibrosis progression
Alena Laschtowitz,
Eric L. Lindberg,
Anna-Maria Liebhoff,
Laura Anne Liebig,
Christian Casar,
Silja Steinmann,
Adrien Guillot,
Jun Xu,
Dorothee Schwinge,
Michael Trauner,
Ansgar Wilhelm Lohse,
Stefan Bonn,
Norbert Hübner,
Christoph Schramm
Affiliations
Alena Laschtowitz
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany; Cardiovascular and Metabolic Sciences, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; Berlin Institute of Health (BIH), Berlin, Germany; European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany; Corresponding authors. Address: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany; Tel.: +49 40 7410 52545 (C. Schramm); Tel.: +49 30 450 630127 (A. Laschtowitz).
Eric L. Lindberg
Cardiovascular and Metabolic Sciences, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; Department of Medicine I, LMU University Hospital, LMU Munich, Munich, Germany; Gene Center, Department of Biochemistry, Ludwig Maximilians Universität, Munich, Germany
Anna-Maria Liebhoff
Institute of Medical Systems Biology, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Laura Anne Liebig
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Cardiovascular and Metabolic Sciences, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany
Christian Casar
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany; Bioinformatics Core, University Medical Center Hamburg-Eppendorf; Hamburg, Germany
Silja Steinmann
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany
Adrien Guillot
Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany
Jun Xu
Department of Biomarker Sciences, Gilead Sciences Inc., San Mateo, California, United States of America
Dorothee Schwinge
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany
Michael Trauner
European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany; Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
Ansgar Wilhelm Lohse
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany
Stefan Bonn
Institute of Medical Systems Biology, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Norbert Hübner
Cardiovascular and Metabolic Sciences, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany; German Center for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany; Charité - Universitätsmedizin Berlin, Berlin, Germany
Christoph Schramm
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; European Reference Network for Hepatological Diseases (ERN-RARE LIVER), Hamburg, Germany; Martin-Zeitz-Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), Hamburg, Germany; Corresponding authors. Address: I.Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Martinistraße 52, 20251 Hamburg, Germany; Tel.: +49 40 7410 52545 (C. Schramm); Tel.: +49 30 450 630127 (A. Laschtowitz).
Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic heterogenous cholangiopathy with unknown etiology where chronic inflammation of the bile ducts leads to multifocal biliary strictures and biliary fibrosis with consecutive cirrhosis development. We here aimed to identify a PSC-specific gene signature associated with biliary fibrosis development. Methods: We performed RNA-sequencing of 47 liver biopsies from people with PSC (n = 16), primary biliary cholangitis (PBC, n = 15), and metabolic dysfunction-associated steatotic liver disease (MASLD, n = 16) with different fibrosis stages to identify a PSC-specific gene signature associated with biliary fibrosis progression. For validation, we compared an external transcriptome data set of liver biopsies from people with PSC (n = 73) with different fibrosis stages (baseline samples from NCT01672853). Results: Differential gene expression analysis of the liver transcriptome from patients with PSC with advanced vs. early fibrosis revealed 431 genes associated with fibrosis development. Of those, 367 were identified as PSC-associated when compared with PBC or MASLD. Validation against an external data set of 73 liver biopsies from patients with PSC with different fibrosis stages led to a condensed set of 150 (out of 367) differentially expressed genes. Cell type specificity assignment of those genes by using published single-cell RNA-Seq data revealed genetic disease drivers expressed by cholangiocytes (e.g. CXCL1, SPP1), fibroblasts, innate, and adaptive immune cells while deconvolution along fibrosis progression of the PSC, PBC, and MASLD samples highlighted an early involvement of macrophage- and neutrophil-associated genes in PSC fibrosis. Conclusions: We reveal a PSC-attributed gene signature associated with biliary fibrosis development that may enable the identification of potential new biomarkers and therapeutic targets in PSC-related fibrogenesis. Impact and implications:: Primary sclerosing cholangitis (PSC) is an inflammatory liver disease that is characterized by multifocal inflammation of bile ducts and subsequent biliary fibrosis. Herein, we identify a PSC-specific gene set of biliary fibrosis progression attributing to a uniquely complex milieu of different cell types, including innate and adaptive immune cells while neutrophils and macrophages showed an earlier involvement in fibrosis initiation in PSC in contrast to PBC and metabolic dysfunction-associated steatotic liver disease. Thus, our unbiased approach lays an important groundwork for further mechanistic studies for research into PSC-specific fibrosis.
