Translational Study

Since more than 10 years, liver regeneration is in the focus of our research interests21. In the course of our investigations, we had several breakthroughs, including the surprising observation that peripheral platelet-derived serotonin is an essential factor for liver regeneration (published in Science22) or the finding that serotonin agonism is able to restore the regenerative deficits of old liver (published in PNAS23). Further, we investigated the different features and mechanisms involved in liver regeneration after various regenerative stimuli including portal vein ligature (PVL) or embolization (PVE) and partial hepatectomy (the standard regeneration model)14, 24. Moreover, we described the molecular changes associated with failed regeneration after the transplantation of marginal grafts25, 26 and successfully translated these findings into the clinic27.

Our current research aims at developing innovative strategies that may ultimately help to expand the treatment of liver tumors through surgery. Within this frame, we have discovered that liver failure due to extensive resection occurs due to a regenerative delay (a p21-dependent mitotic arrest), which we were able to correct (Lehmann et al., Gastroenterology). Likewise, we are successfully testing agents that can boost the regenerative response of marginal remnants, either by promoting progression through the cell cycle (Tschuor et al., unpublished) or by improving the sinusoidal perfusion (Schlegel et al., unpublished). These agents may well be serious candidates for a next-generation-approach in extending the application of liver surgery.

All of these projects are based on the successful design of novel animal models. Complex surgery in mouse - still the model system of choice - is very challenging, however we can rely on the technical expertise of our uniquely skilled microsurgeon (Dr Y Tian). We were able to introduce a series of novel mouse models, including those for arterialized orthotopic liver transplantation28, transplantation of critically small grafts26, hepatectomies leading to critically small future remnants (Lehmann et al., under revision), or models of liver regeneration induced by PVE and PVL14, 24. Likewise, we now have established syngeneic mouse models of liver cancer and CRC liver metastasis.

ALPPS has been introduced to the clinic only very recently2, 9, and accordingly no animal ALPPS model exists. In a concerted effort, we now have at hands a first mouse model of ALPPS. Whilst this is an ongoing project, our preliminary data has demonstrated the feasibility of our approach.