Acquisition of epithelial plasticity in human chronic liver disease

Christopher Gribben, Vasileios Galanakis, Alexander Calderwood, Eleanor C. Williams, Ruben Chazarra-Gil, Miguel Larraz, Carla Frau, Tobias Puengel, Adrien Guillot, Foad J. Rouhani, Krishnaa Mahbubani, Edmund Godfrey, Susan E. Davies, Emmanouil Athanasiadis, Kourosh Saeb-Parsy, Frank Tacke, Michael Allison (), Irina Mohorianu () and Ludovic Vallier ()
Additional contact information
Christopher Gribben: University of Cambridge
Vasileios Galanakis: University of Cambridge
Alexander Calderwood: University of Cambridge
Eleanor C. Williams: University of Cambridge
Ruben Chazarra-Gil: University of Cambridge
Miguel Larraz: University of Cambridge
Carla Frau: Berlin Institute of Health Centre for Regenerative Therapies
Tobias Puengel: Charité Universitätsmedizin Berlin
Adrien Guillot: Charité Universitätsmedizin Berlin
Foad J. Rouhani: Francis Crick Institute
Krishnaa Mahbubani: University of Cambridge
Edmund Godfrey: Addenbrooke’s Hospital
Susan E. Davies: Cambridge University Hospitals NHS Foundation Trust
Emmanouil Athanasiadis: Biomedical Research Foundation of the Academy of Athens
Kourosh Saeb-Parsy: University of Cambridge
Frank Tacke: Charité Universitätsmedizin Berlin
Michael Allison: Wellcome Genome Campus
Irina Mohorianu: University of Cambridge
Ludovic Vallier: University of Cambridge

Nature, 2024, vol. 630, issue 8015, 166-173

Abstract: 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 characterized1–4, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07465-2

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