Mammals have a poor regenerative capacity as compared to distant vertebrate relatives, such as salamanders that can regenerate limbs and organs throughout life. The ability to regenerate organs most probably originated as a derivative of normal developmental growth, rather than as a novel adaptive trait. All vertebrates display an abundant capacity for organ growth in the neonatal window, but only a restricted set of species can efficiently reactivate the neonatal organ growth program in adulthood. Sadly, the human is not one of these species, and this means that human regenerative medicine represents an enormous challenge. The liver is one of the only organs that has maintained some regenerative capacity in adult mammals. The goal of our liver regeneration research is to understand the molecular mechanisms driving liver regeneration so well that we can manipulate the molecular circuits coordinating tissue growth to boost the regenerative capacity of the liver. In both humans and rodents there is a ten-fold increase in liver mass between birth and young adulthood. The neonatal liver growth capacity can increase further, as neonatal mice even survive a partial hepatectomy. We hypothesize that the coordinated proliferation of liver cells is orchestrated by evolutionary conserved molecular circuits that ensures liver function and avoids organ failure during the rapid neonatal tissue growth. The adult liver has better re-growth capacity than other organs, but this remains far below the neonatal growth capacity. The adult liver can replenish up to 70% of its mass after surgical resection, allowing the removal of liver tumors. However, for a liver resection to be safe, the liver remnant should be at least 30% of the initial liver volume, putting the maximal adult liver growth capacity at a three-fold increase. If the remaining liver is too small, the patient has high risk of developing the Small-For-Size Syndrome (SFSS), a post-operative failure causing death of one in three patients. For decades scientists have tried to boost hepatocyte proliferation to accelerate liver regeneration. However, while signals involved in hepatocyte proliferation are known, all attempts to pharmacologically augment regeneration by boosting hepatocyte proliferation have so far failed. In our research, we will step away from the conventional hepatocyte-centric view of liver regeneration. We propose a paradigm shift in which we consider the liver as a repeated structure of integrated liver modules and hypothesize that the key to successful liver regeneration is to maintain the integrity of each individual liver module, as this will be vital to maintain the function of liver cells during organ growth. 

We have the ambition to tackle some of the major outstanding fundamental questions at the heart of macrophage biology: do macrophages, tissue-resident or recruited, “remember” an inflammatory insult through epigenetic modifications and respond differently to a secondary insult? Do cells that surround the macrophage and make up their cellular niche, also bear an epigenetic memory of this primary insult and does this result in a rewired macrophage-niche crosstalk? We will study the functionality of resident macrophages and their respective structural niches after disease resolution and will investigate whether a transcriptional or epigenetic memory of previous insults is retained in these cells. Using cellular fate-mapping we will distinguish the resident macrophages that were already present before the insult and survived the inflammation and the resident macrophages that developed from monocytes that engrafted in the tissues during the inflammation. We will also investigate whether the molecular basis for the persistent altered macrophage responses after inflammation consists of pathogenic cell-cell circuits between the macrophages and the cells constituting their niche. We will investigate whether: (i) resident macrophages and their niche "remember" previous inflammatory episodes, (ii) this "macrophage niche memory" affects the homeostatic function of macrophages and their response to subsequent insults, (iii) resetting the homeostatic cell-cell circuits within the macrophage niche prevents macrophage dysregulation and disease susceptibility. We collaborate with multiple teams on this topic: the Scott team to track the memory in the MAFLD liver, the Van Ginderachter & Movahedi team to track the memory after a trypanosome infection (Musrati et al. J Hepatology 2024) and the Guy Boeckxstaens team to track the memory after intestinal inflammatory events.