近日，德国马克斯·普朗克分子细胞生物学和遗传学研究所Meritxell Huch小组的最新研究揭示了人门静脉周围肝组织的体外重组。相关论文于2025年12月17日发表在《自然》杂志上。

在这里，研究小组首先从28名不同的患者身上开发了人肝细胞类器官（h-HepOrgs）。患者源性肝细胞类器官在体外维持了肝细胞的长期扩张，维持了患者特异性基因表达和体内组织的胆管特征和功能。移植后，扩增的h-HepOrgs挽救了肝脏疾病单主题模型的表型。通过将h-HepOrgs与门静脉间质及其先前发表的胆管细胞类器官相结合，该研究组生成了具有患者特异性的门静脉周围肝组装体，这些组装体保留了门静脉周围肝组织的组织学排列、基因表达和细胞相互作用，胆管细胞和间质嵌入肝细胞实质。研究团队利用这个平台来模拟胆道纤维化的各个方面。他们的人类门静脉周围肝脏组装体系统为研究人类肝脏病理生理、加速药物开发、实现早期诊断和推进个性化医疗提供了一个新的体外平台。

据了解，复杂的多细胞人体体外系统的发展为疾病建模、推进药物发现和组织工程提供了巨大的希望。在肝脏中，尽管已经确定了参与肝脏再生的关键信号通路，但直接从新鲜患者组织中体外扩增人肝细胞尚未实现，这限制了体外模拟肝脏复合结构的可能性。

附：英文原文

Title: Human assembloids recapitulate periportal liver tissue in vitro

Author: Yuan, Lei, Dawka, Sagarika, Kim, Yohan, Liebert, Anke, Rost, Fabian, Arnes-Benito, Robert, Baenke, Franziska, Gtz, Christina, Tsang, David Long Hin, Schuhmann, Andrea, Shevchenko, Anna, Rezende de Castro, Roberta, Kim, Seunghee, Sljukic, Aleksandra, Dowbaj, Anna M., Shevchenko, Andrej, Seehofer, Daniel, Choi, Dongho, Damm, Georg, Stange, Daniel E., Huch, Meritxell

Issue&Volume: 2025-12-17

Abstract: The development of complex multicellular human in vitro systems holds great promise for modelling disease and advancing drug discovery and tissue engineering1. In the liver, despite the identification of key signalling pathways involved in hepatic regeneration2,3, in vitro expansion of human hepatocytes directly from fresh patient tissue has not yet been achieved, limiting the possibility of modelling liver composite structures in vitro. Here we first developed human hepatocyte organoids (h-HepOrgs) from 28 different patients. Patient-derived hepatocyte organoids sustained long-term expansion of hepatocytes in vitro and maintained patient-specific gene expression and bile canaliculus features and function of the in vivo tissue. After transplantation, expanded h-HepOrgs rescued the phenotype of a mouse model of liver disease. By combining h-HepOrgs with portal mesenchyme and our previously published cholangiocyte organoids4,5,6, we generated patient-specific periportal liver assembloids that retain the histological arrangement, gene expression and cell interactions of periportal liver tissue, with cholangiocytes and mesenchyme embedded in the hepatocyte parenchyma. We leveraged this platform to model aspects of biliary fibrosis. Our human periportal liver assembloid system represents a novel in vitro platform to investigate human liver pathophysiology, accelerate drug development, enable early diagnosis and advance personalized medicine.

DOI: 10.1038/s41586-025-09884-1

Source: https://www.nature.com/articles/s41586-025-09884-1