Cell differentiation and plasticity in the healthy and diseased liver

Grün Lab

The liver is the major metabolic organ of the body. Liver malignancies, such as fatty liver disease, liver cancer, or Hepatitis, are on the rise, in particular in western societies as a consequence of an unhealthy lifestyle. To repair tissue damage, the liver has developed and extraordinary regenerative capacity. This is best exemplified by the ability of the liver to regrow to its full size after surgical removal of up to 75% of its original mass. In the past, a large body of research has emerged revealing distinct pathways of regeneration. For instance, liver resection and acute liver damage was found to initiate proliferation of hepatocytes, while upon chronic liver damage or suppression of hepatocyte proliferation parenchymal cells regenerate from the bile duct epithelium. However, our understanding of the molecular and cellular processes controlling cell state changes in the liver during health and disease is far from complete. With the recent availability of single-cell resolution methods, in particular single-cell RNA-seq, it became possible to study liver cell types with high resolution.

Using quantitative single-cell methods we are investigating the cellular composition of the liver in mouse liver damage models and human samples derived from healthy and diseased individuals. Our goal is to decipher pathways of cellular differentiation maintaining the tissue under homeostatic conditions and to elucidate perturbations of these pathways upon liver disease such as damage-induced cell type plasticity (Aizarani et al.,  Nature, 2020). We study fundamental processes of regeneration and organ growth in the mouse model and use liver organoids derived from human samples for functional studies of these pathways.

Our strategy has a particular focus on the role of cell-cell communication across the epithelial, immune, and mesenchymal compartment involved in the control of cellular differentiation and cell state plasticity in the liver.

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