Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
Hepatology. 2019 May;69(5):2180-2195. doi: 10.1002/hep.30472. Epub 2019 Mar 12.
Chronic liver diseases are characterized by the expansion of ductular reaction (DR) cells and the expression of liver progenitor cell (LPC) markers. In alcoholic hepatitis (AH), the degree of DR expansion correlates with disease progression and short-term survival. However, little is known about the biological properties of DR cells, their impact on the pathogenesis of human liver disease, and their contribution to tissue repair. In this study, we have evaluated the transcriptomic profile of DR cells by laser capture microdissection in patients with AH and assessed its association with disease progression. The transcriptome analysis of cytokeratin 7-positive (KRT7 ) DR cells uncovered intrinsic gene pathways expressed in DR and genes associated with alcoholic liver disease progression. Importantly, DR presented a proinflammatory profile with expression of neutrophil recruiting C-X-C motif chemokine ligand (CXC) and C-C motif chemokine ligand chemokines. Moreover, LPC markers correlated with liver expression and circulating levels of inflammatory mediators such as CXCL5. Histologically, DR was associated with neutrophil infiltration at the periportal area. In order to model the DR and to assess its functional role, we generated LPC organoids derived from patients with cirrhosis. Liver organoids mimicked the transcriptomic and proinflammatory profile of DR cells. Conditioned medium from organoids induced neutrophil migration and enhanced cytokine expression in neutrophils. Likewise, neutrophils promoted the proinflammatory profile and the expression of chemokines of liver organoids. Conclusion: Transcriptomic and functional analysis of KRT7 cells indicate that DR has a proinflammatory profile and promote neutrophil recruitment. These results indicate that DR may be involved in the liver inflammatory response in AH, and suggest that therapeutic strategies targeting DR cells may be useful to mitigate the inflammatory cell recruitment in AH.
慢性肝脏疾病的特征是胆管反应 (DR) 细胞的扩张和肝祖细胞 (LPC) 标志物的表达。在酒精性肝炎 (AH) 中，DR 扩张的程度与疾病进展和短期生存相关。然而，对于 DR 细胞的生物学特性、它们对人类肝脏疾病发病机制的影响以及它们对组织修复的贡献知之甚少。在这项研究中，我们通过激光捕获微解剖评估了 AH 患者 DR 细胞的转录组谱，并评估了其与疾病进展的关联。细胞角蛋白 7 阳性 (KRT7) DR 细胞的转录组分析揭示了 DR 中表达的内在基因途径和与酒精性肝病进展相关的基因。重要的是，DR 呈现出促炎表型，表达中性粒细胞募集 C-X-C 基序趋化因子配体 (CXC) 和 C-C 基序趋化因子配体趋化因子。此外，LPC 标志物与肝表达和循环中炎症介质如 CXCL5 相关。组织学上，DR 与门脉周围区域的中性粒细胞浸润有关。为了模拟 DR 并评估其功能作用，我们从肝硬化患者中生成了 LPC 类器官。肝类器官模拟了 DR 细胞的转录组和促炎表型。类器官的条件培养基诱导中性粒细胞迁移并增强中性粒细胞中细胞因子的表达。同样，中性粒细胞促进了肝类器官的促炎表型和趋化因子的表达。结论：KRT7 细胞的转录组和功能分析表明，DR 具有促炎表型并促进中性粒细胞募集。这些结果表明，DR 可能参与 AH 中的肝炎症反应，并表明靶向 DR 细胞的治疗策略可能有助于减轻 AH 中的炎症细胞募集。
