Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
J Pathol. 2019 May;248(1):66-76. doi: 10.1002/path.5228. Epub 2019 Jan 30.
Ductular reaction (DR) represents the activation of hepatic progenitor cells (HPCs) and has been associated with features of advanced chronic liver disease; yet it is not clear whether these cells contribute to disease progression and how the composition of their micro-environment differs depending on the aetiology. This study aimed to identify HPC-associated signalling pathways relevant in different chronic liver diseases using a high-throughput sequencing approach. DR/HPCs were isolated using laser microdissection from patient samples diagnosed with HCV or primary sclerosing cholangitis (PSC), as models for hepatocellular or biliary regeneration. Key signals were validated at the protein level for a cohort of 56 patients (20 early and 36 advanced stage). In total, 330 genes were significantly differentially expressed between the HPCs in HCV and PSC. Recruitment and homing of inflammatory cells were distinctly different depending on the aetiology. HPCs in PSC were characterised by a response to oxidative stress (e.g. JUN, VNN1) and neutrophil-attractant chemokines (CXCL5, CXCL6, IL-8), whereas HPCs in HCV were identified by T- and B-lymphocyte infiltration. Moreover, we found that communication between HPCs and macrophages was aetiology driven. In PSC, a high frequency of CCL28-positive macrophages was observed in the portal infiltrate, already in early disease in the absence of advanced fibrosis, while in HCV, HPCs showed a strong expression of the macrophage scavenger receptor MARCO. Interestingly, DR/HPCs in PSC showed more deposition of ECM (e.g. FN1, LAMC2, collagens) compared to HCV, where an increase of pro-invasive genes (e.g. PDGFRA, IGF2) was observed. Additionally, endothelial cells in the vicinity of DR/HPCs showed differential immunopositivity (e.g. IGF2 and INHBA expression). In conclusion, our data shine light on the role of DR/HPCs in immune signalling, fibrogenesis and angiogenesis in chronic liver disease. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
胆管反应 (DR) 代表肝祖细胞 (HPC) 的激活，与晚期慢性肝病的特征有关；然而，尚不清楚这些细胞是否有助于疾病进展，以及它们的微环境组成如何因病因而异。本研究旨在使用高通量测序方法鉴定与不同慢性肝病相关的 HPC 相关信号通路。使用激光显微切割从诊断为 HCV 或原发性硬化性胆管炎 (PSC) 的患者样本中分离 DR/HPC，作为肝细胞或胆管再生的模型。对 56 名患者 (20 名早期和 36 名晚期) 的队列进行了关键信号的蛋白质水平验证。总共，在 HCV 和 PSC 的 HPC 之间有 330 个基因差异显著表达。根据病因，炎症细胞的募集和归巢明显不同。PSC 中的 HPC 以对氧化应激的反应为特征 (例如 JUN、VNN1) 和中性粒细胞趋化因子 (CXCL5、CXCL6、IL-8)，而 HCV 中的 HPC 则以 T 和 B 淋巴细胞浸润为特征。此外，我们发现 HPC 与巨噬细胞之间的通讯是病因驱动的。在 PSC 中，在早期疾病中已经观察到门静脉浸润中存在高频率的 CCL28 阳性巨噬细胞，而在 HCV 中，HPC 表现出巨噬细胞清道夫受体 MARCO 的强烈表达。有趣的是，与 HCV 相比，PSC 中的 DR/HPC 表现出更多的细胞外基质 (例如 FN1、LAMC2、胶原) 沉积，而在 HCV 中，观察到促侵袭基因 (例如 PDGFRA、IGF2) 的增加。此外，DR/HPC 附近的内皮细胞表现出不同的免疫阳性 (例如 IGF2 和 INHBA 表达)。总之，我们的数据揭示了 DR/HPC 在慢性肝病中的免疫信号、纤维化和血管生成中的作用。版权所有 © 2018 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd. 出版
