英国剑桥大学Ludovic Vallier等研究人员合作揭示了人类慢性肝病上皮可塑性的获得。2024年5月22日，《自然》杂志在线发表了这一最新研究成果。

研究人员表示，对于许多成人人体器官来说，慢性疾病期间的组织再生仍然是一个有争议的话题。在动物模型中很容易观察到再生过程，其基本机制也逐渐得到了很好的表征，但技术上的挑战和伦理方面的问题限制了这些结果在人类身上的验证。

研究人员决定在肝脏方面解决这一难题。肝脏在急性损伤后显示出卓越的再生能力，但肝脏在损伤复发情况下的再生能力仍有待充分证明。研究人员对47例不同阶段代谢功能障碍相关脂肪肝患者的肝脏活检组织进行了单核RNA测序（snRNA-seq），以建立疾病进展过程中的肝脏细胞图谱。然后，研究人员将这些单细胞级数据与先进的三维成像技术相结合，揭示了肝脏结构的深刻变化。肝细胞失去了分区，胆道树发生了相当大的重组。

更重要的是，该研究揭示了肝细胞和胆管细胞之间发生的转分化事件，而不存在成体干细胞或发育祖细胞激活。利用胆管细胞类器官进行的详细分析和功能验证证实了PI3K-AKT-mTOR通路在这一过程中的重要性，从而将这种可塑性的获得与胰岛素信号联系起来。总之，这些数据表明，慢性损伤创造了一种诱导人体器官细胞可塑性的环境，了解这一过程的内在机制可为慢性疾病的治疗开辟新的途径。

附：英文原文

Title: Acquisition of epithelial plasticity in human chronic liver disease

Author: Gribben, Christopher, Galanakis, Vasileios, Calderwood, Alexander, Williams, Eleanor C., Chazarra-Gil, Ruben, Larraz, Miguel, Frau, Carla, Puengel, Tobias, Guillot, Adrien, Rouhani, Foad J., Mahbubani, Krishnaa, Godfrey, Edmund, Davies, Susan E., Athanasiadis, Emmanouil, Saeb-Parsy, Kourosh, Tacke, Frank, Allison, Michael, Mohorianu, Irina, Vallier, Ludovic

Issue&Volume: 2024-05-22

Abstract: For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized1,2,3,4, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K–AKT–mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases.

DOI: 10.1038/s41586-024-07465-2

Source: https://www.nature.com/articles/s41586-024-07465-2