Acquisition of epithelial plasticity in human chronic liver disease

• Published in: Nature (London) Vol. 630; no. 8015; pp. 166 - 173
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.06.2024; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/100; 13/106; 13/51; 14/19; 45/100; 45/91; 631/532/2128; 631/532/489; AKT protein; Animal models; Biliary tract; Biliary Tract - cytology; Biliary Tract - metabolism; Biliary Tract - pathology; Biopsy; Cell activation; Cell Plasticity; Cell Transdifferentiation; Chronic Disease; Chronic illnesses; Disease Progression; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Experiments; Gene sequencing; Hepatocytes; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - pathology; Humanities and Social Sciences; Humans; Injuries; Insulin - metabolism; Keratin; Liver; Liver - cytology; Liver - metabolism; Liver - pathology; Liver cirrhosis; Liver diseases; Liver Diseases - metabolism; Liver Diseases - pathology; Liver Regeneration; Metabolism; multidisciplinary; Organoids; Organoids - metabolism; Organoids - pathology; Organs; Phosphatidylinositol 3-Kinases - metabolism; Plastic foam; Plastic properties; Plasticity; Progenitor cells; Proto-Oncogene Proteins c-akt - metabolism; Quality control; Regeneration (physiology); RNA-Seq; Science; Science (multidisciplinary); Signal Transduction; Single-Cell Analysis; snRNA; Stem cells; Three dimensional imaging; Tissue engineering; TOR Serine-Threonine Kinases - metabolism; Zonation
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07465-2

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 – 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. Single-cell RNA sequencing and 3D imaging have revealed the cellular changes and structural reorganization that occur during the progression of human chronic liver disease and as the liver attempts to regenerate.