Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
Cell Death Dis. 2020 Mar 23;11(3):199. doi: 10.1038/s41419-020-2372-9.
Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvβ6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvβ6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.
肝细胞在慢性损伤的刺激下发生上皮-间充质转分化（EMT）为胆管上皮细胞（BECs），从而促进肝脏再生。直到现在，肝细胞向胆管上皮细胞转分化的机制仍未被探索。在肝脏纤维化的小鼠模型中，纤维化的肝脏中观察到明显的 BEC 反应，肌成纤维细胞的耗竭显著减弱了 BEC 的扩张。然后，在肝细胞命运追踪小鼠模型中，我们证明了成熟的肝细胞在纤维化的肝脏中转分化为胆管 BEC，肌成纤维细胞的耗竭减少了肝细胞向胆管的转分化。最后，我们研究了转分化的机制。肌成纤维细胞分泌富含层粘连蛋白的细胞外基质，然后层粘连蛋白通过 ɑvβ6 整合素诱导肝细胞向胆管上皮细胞转分化。因此，我们的结果表明，肌成纤维细胞通过层粘连蛋白-ɑvβ6 整合素诱导成熟的肝细胞转分化为胆管 BEC，这表明通过修饰特定的微环境可以改善纤维化肝脏的再生。
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