LegoLiver · (Re)constructing the liver, brick by brick

Mammals display an abundant capacity for organ growth in the neonatal window but lose this capacity in adulthood. The adult liver maintains some regenerative capacity, but this remains far below the neonatal growth capacity. The adult liver can replenish up to 70% of its mass after surgical resection. However, resection of larger volumes induces liver failure, which causes death of one in three patients. For decades hepatologists have tried to pharmacologically augment hepatocyte proliferation to improve liver regeneration, yet all these attempts have failed. Our recent liver cell atlas revealed the modular architecture of the liver, with each module containing a dedicated macrophage and stromal cell. The primary hepatic module is composed of 4 cell types: hepatocytes, sinusoidal endothelial cells, stellate cells and Kupffer cells. We studied this 4-cell-circuit across seven species and found that throughout evolution these cells became so interdependent that they operate as one interconnected functional module. Stepping away from the conventional hepatocyte-centric view of liver regeneration, we propose a paradigm shift in which we hypothesize that the key to successful liver regeneration is to maintain the integrity of each liver module. Our preliminary data indicate that multiplication of neonatal cells happens synchronously, while adult generation is characterized by uncoupled multiplication of liver cells. We will track the multiplication of liver cells in space and time across different biological models, during the neonatal window and in adults upon surgery, to identify the mechanisms that underlie the synchronous multiplication of neonatal liver cells. We will develop high-throughput functional in vivo screens to manipulate the hepatic molecular circuits and identify pathways that can boost liver regeneration and maintain cellular functionality, with as ultimate goal to identify novel classes of therapeutic targets that can boost liver regeneration.