Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Cell Stem Cell. 2018 Jul 5;23(1):114-122.e3. doi: 10.1016/j.stem.2018.05.022. Epub 2018 Jun 21.
Chronic liver injury can cause cirrhosis and impaired liver regeneration, impairing organ function. Adult livers can regenerate in response to parenchymal insults, and multiple cellular sources have been reported to contribute to this response. In this study, we modeled human chronic liver injuries, in which such responses are blunted, without genetic manipulations, and assessed potential contributions of non-parenchymal cells (NPCs) to hepatocyte regeneration. We show that NPC-derived hepatocytes replenish a large fraction of the liver parenchyma following severe injuries induced by long-term thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) treatment. Through lineage tracing of biliary epithelial cells (BECs), we show that BECs are a source of new hepatocytes and gain an Hnf4αCK19 bi-phenotypic state in periportal regions and fibrotic septa. Bi-phenotypic cells were also detected in cirrhotic human livers. Together, these data provide further support for hepatocyte regeneration from BECs without genetic interventions and show their cellular plasticity during severe liver injury.
慢性肝损伤可导致肝硬化和肝再生受损，从而损害器官功能。成人肝脏可以对实质损伤作出反应而再生，并且已经报道了多种细胞来源有助于这种反应。在这项研究中，我们在没有遗传操作的情况下模拟了人类慢性肝损伤，其中这种反应受到了抑制，并评估了非实质细胞（NPC）对肝细胞再生的潜在贡献。我们发现，在长期使用硫代乙酰胺（TAA）或 3,5-二乙氧羰基-1,4-二氢吡啶（DDC）处理引起严重损伤后，NPC 来源的肝细胞可补充大部分肝实质。通过对胆管上皮细胞（BEC）的谱系追踪，我们发现 BEC 是新肝细胞的来源，并在门脉周围区域和纤维性间隔中获得了 Hnf4αCK19 双表型状态。在肝硬化的人类肝脏中也检测到了双表型细胞。这些数据共同为没有遗传干预的情况下 BEC 从再生提供了进一步的支持，并显示了它们在严重肝损伤期间的细胞可塑性。
