Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Research Institute of Internal Medicine, Division of Surgery and Specialized Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Dig Dis Sci. 2024 Oct;69(10):3810-3823. doi: 10.1007/s10620-024-08570-y. Epub 2024 Aug 19.
Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disorder without effective medical treatment which is characterized by inflammation and fibrotic structures around the bile ducts. Biliary epithelial cells (cholangiocytes) are the target and potential disease drivers in PSC, yet little is known if cholangiocytes from PSC patients differ from non-PSC controls. To characterize cholangiocytes at early rather than end-stage disease, cholangiocyte organoids (COs) were derived from diseased bile ducts of PSC patients and compared to organoids generated from disease controls.
Cholangiocytes were obtained during endoscopic retrograde cholangiopancreatography (ERCP) brushing of diseased bile duct areas and expanded as organoids using previously established culture methods. Stable CO lines were analyzed for cell type identity, basic cholangiocyte function, and transcriptomic signature.
We demonstrate that cholangiocytes, derived from the damaged area within the bile ducts of PSC patients, can be expanded in culture without displaying functional or genetic disease-related features. We further show that COs from patients who later were diagnosed with dysplasia exhibit higher expression of the cancer-associated genes PGC, FXYD2, MIR4435-2HG, and HES1.
Our results demonstrate that PSC organoids are largely similar to control organoids after culture and highlight the significance of COs as a tool for regenerative medicine approaches as well as their potential for discovering new potential biomarkers for diagnosing cholangiocarcinoma.
原发性硬化性胆管炎（PSC）是一种慢性炎症性肝病，目前尚无有效的治疗方法，其特征为胆管周围的炎症和纤维化结构。胆管上皮细胞（胆管细胞）是 PSC 的靶细胞和潜在疾病驱动因素，但人们对 PSC 患者的胆管细胞是否与非 PSC 对照者不同知之甚少。为了在早期而不是晚期疾病中对胆管细胞进行特征描述，我们从 PSC 患者的病变胆管中获得了胆管细胞原代培养物（CO），并将其与来自疾病对照者的原代培养物进行了比较。
通过内镜逆行胰胆管造影术（ERCP）刷取病变胆管区域的胆汁获得胆管细胞，并使用先前建立的培养方法将其扩增为 CO。对稳定的 CO 系进行细胞类型鉴定、基本胆管细胞功能和转录组特征分析。
我们证明，源自 PSC 患者胆管损伤区域的胆管细胞可以在培养中扩增，而不表现出功能或遗传疾病相关特征。我们进一步表明，后来被诊断为异型增生的患者的 CO 表现出更高水平的癌症相关基因 PGC、FXYD2、MIR4435-2HG 和 HES1 的表达。
我们的结果表明，PSC CO 在培养后与对照 CO 基本相似，并强调了 CO 作为再生医学方法的工具的重要性，以及它们在发现诊断胆管癌的新潜在生物标志物方面的潜力。
