See editorial on page 849.The cellular origin of human intrahepatic cholangiocarcinoma (iCCA) is actively debated with the goal to improve diagnosis and therapy.^1,2 The current pathological classification distinguishes large and small bile duct types based on presumed cellular origin.³ Large bile duct–type iCCAs resemble extrahepatic (perihilar and distal) cholangiocarcinomas in location, morphology, and intraductal or periductal growth pattern, indicating origin from cholangiocytes in segmental bile ducts, although unipotent progenitor cells in adjacent peribiliary glands may contribute. Small bile duct–type iCCAs share features with hepatocellular carcinoma (HCC), including peripheral location and mass-forming growth pattern, and are therefore thought to derive not only from cholangiocytes in septal or interlobular bile ducts but also from bipotent progenitor cells located where bile ducts connect to hepatocyte canaliculi. Hepatocytes acquire biliary characteristics in the process of injury-induced metaplasia,² suggesting they could also generate iCCA. Indeed, common diseases affecting hepatocytes—hepatitis B and C, alcoholic liver disease, and steatotic liver disease—are risk factors for iCCA, which may explain its increasing incidence.¹ However, despite evidence from lineage tracing in mice^4,5 and supportive genetic and epigenetic features in iCCAs resected from patients,⁶ a hepatocyte origin is not considered in clinical diagnosis, classification, or therapy,³ prompting us to generate direct evidence using normal primary human hepatocytes (phHeps).

中文翻译：

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人肝细胞可导致肝内胆管癌


见第 849 页的社论。人肝内胆管癌 （iCCA） 的细胞起源正在积极争论，以改善诊断和治疗。¹² 目前的病理分类根据假定的细胞起源来区分大胆管类型和小胆管类型。³ 大胆管型 iCCA 在位置、形态和导管内或导管周围生长模式上类似于肝外（肺门周围和远端）胆管癌，表明起源于节段性胆管中的胆管细胞，尽管邻近胆管周围的单能祖细胞可能起作用。小胆管型 iCCA 与肝细胞癌 （HCC） 具有共同特征，包括外周位置和肿块形成生长模式，因此被认为不仅来源于间隔或小叶间胆管中的胆管细胞，还来源于位于胆管与肝细胞小管相连处的双能祖细胞。肝细胞在损伤诱导的化生过程中获得胆道特征，² 表明它们也可以产生 iCCA。事实上，影响肝细胞的常见疾病（乙型肝炎和丙型肝炎、酒精性肝病和脂肪性肝病）是 iCCA 的危险因素，这可能解释了其发病率增加的原因。¹ 然而，尽管小鼠的谱系追踪证据⁴⁵ 以及从患者身上切除的 iCCA 的支持性遗传和表观遗传学特征，⁶ 但在临床诊断、分类或治疗中并未考虑肝细胞起源，³ 促使我们使用正常的原代人肝细胞 （phHeps） 生成直接证据。