Laschtowitz Alena, Lindberg Eric L, Liebhoff Anna-Maria, Liebig Laura Anne, Casar Christian, Steinmann Silja, Guillot Adrien, Xu Jun, Schwinge Dorothee, Trauner Michael, Lohse Ansgar Wilhelm, Bonn Stefan, Hübner Norbert, Schramm Christoph
Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
JHEP Rep. 2024 Nov 12;7(3):101267. doi: 10.1016/j.jhepr.2024.101267. eCollection 2025 Mar.
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.
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).
Differential gene expression analysis of the liver transcriptome from patients with PSC with advanced 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. ), 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.
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.
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.
原发性硬化性胆管炎（PSC）是一种病因不明的慢性异质性胆管病，胆管的慢性炎症导致多灶性胆管狭窄和胆管纤维化，并继而发展为肝硬化。我们旨在确定与胆管纤维化发展相关的PSC特异性基因特征。
我们对47例来自原发性硬化性胆管炎患者（n = 16）、原发性胆汁性胆管炎患者（PBC，n = 15）和代谢功能障碍相关脂肪性肝病患者（MASLD，n = 16）且处于不同纤维化阶段的肝活检组织进行RNA测序，以确定与胆管纤维化进展相关的PSC特异性基因特征。为进行验证，我们将来自不同纤维化阶段的原发性硬化性胆管炎患者（n = 73）患者肝活检组织的外部转录组数据集（来自NCT01672853的基线样本）进行了比较。
对处于早期或晚期纤维化的原发性硬化性胆管炎患者的肝脏转录组进行差异基因表达分析，发现431个与纤维化发展相关的基因。其中，与原发性胆汁性胆管炎或代谢功能障碍相关脂肪性肝病相比，有367个基因被确定为与原发性硬化性胆管炎相关。针对来自不同纤维化阶段的73例原发性硬化性胆管炎患者肝活检组织的外部数据集进行验证，得到了一组精简的150个（共367个）差异表达基因。通过使用已发表的单细胞RNA测序数据对这些基因进行细胞类型特异性分配，揭示了胆管细胞（如……）、成纤维细胞、先天性和适应性免疫细胞表达的遗传性疾病驱动因素，而对原发性硬化性胆管炎、原发性胆汁性胆管炎和代谢功能障碍相关脂肪性肝病样本沿纤维化进展进行反卷积分析，突出了巨噬细胞和中性粒细胞相关基因在原发性硬化性胆管炎纤维化早期的参与情况。
我们揭示了一种与胆管纤维化发展相关的原发性硬化性胆管炎特异性基因特征，这可能有助于识别原发性硬化性胆管炎相关纤维化形成中潜在的新生物标志物和治疗靶点。
原发性硬化性胆管炎（PSC）是一种炎症性肝病，其特征是胆管多灶性炎症及随后的胆管纤维化。在此，我们确定了一组原发性硬化性胆管炎特异性的胆管纤维化进展基因集，这归因于不同细胞类型的独特复杂环境，包括先天性和适应性免疫细胞，而与原发性胆汁性胆管炎和代谢功能障碍相关脂肪性肝病相比，中性粒细胞和巨噬细胞在原发性硬化性胆管炎纤维化起始阶段更早参与其中。因此，我们的无偏倚方法为进一步研究原发性硬化性胆管炎特异性纤维化的机制奠定了重要基础。
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