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 characterized^1,2,3,4, 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.

对于许多成人器官来说，慢性疾病期间的组织再生仍然是一个有争议的话题。再生过程在动物模型中很容易观察到，并且其潜在机制正在得到很好的表征 ^1,2,3,4 ，但技术挑战和伦理方面限制了这些结果在人类中的验证。我们决定从肝脏方面解决这个难题。该器官在急性损伤后表现出非凡的再生能力，尽管在反复损伤的情况下肝脏再生仍有待充分证明。在这里，我们对来自代谢功能障碍相关脂肪性肝病不同阶段的患者的 47 例肝活检进行了单核 RNA 测序 (snRNA-seq)，以建立疾病进展期间肝脏的细胞图谱。然后，我们将这些单细胞水平的数据与先进的 3D 成像相结合，揭示肝脏结构的深刻变化。肝细胞失去分区，胆管树发生大量重组。更重要的是，我们的研究揭示了在不存在成体干细胞或发育祖细胞激活的情况下肝细胞和胆管细胞之间发生的转分化事件。使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 通路在此过程中的重要性，从而将这种可塑性的获得与胰岛素信号传导联系起来。总之，我们的数据表明，慢性损伤创造了一个诱导人体器官细胞可塑性的环境，了解这一过程的潜在机制可以为慢性疾病的治疗开辟新的治疗途径。