The liver is a highly regenerative organ. This property is solicited after resection of liver tissue containing tumors. However, resection of large volumes of liver carries the risk of post-hepatectomy liver failure known as the small-for-size-syndrome (SFFS), which causes death of one in three patients. The novel two-step ALPPS surgery achieves a successful liver regeneration in patients with an otherwise insufficient-for-survival liver remnant, yet at the cost of a risky surgery. We do not know which molecular mechanisms underlie the rescued regeneration in ALPPS. For decades scientists have tried to boost hepatocyte proliferation to improve liver regeneration. However, all attempts to pharmacologically augment regeneration by boosting hepatocyte proliferation have failed. In this LSEC-Regen project we propose a paradigm shift from the conventional hepatocyte-centric view on liver regeneration: we hypothesize that the key to successful regeneration is to maintain the vascularization in the regenerating liver. The LSEC-Regen project will apply cutting-edge single-cell and spatial technologies on liver samples from mice undergoing classical partial hepatectomy, SFSS or ALPPS-rescued regeneration. By tracking the cell-cell interactions in space and time in parallel in these 3 models, we will unravel which molecular mechanisms rescue the regeneration process during ALPPS and based on this we hope to develop preclinically interventional strategies that can prevent SFSS.