Origin and fate of liver progenitor cells

(eng) The liver has the extraordinary capacity to self-regenerate following acute and chronic injury. Nevertheless, in terminal-stages of liver disease, this capacity is abrogated and liver transplantation is the only possible rescue. These days, the long-standing shortage of donor livers has encouraged researchers to progress in the development of new therapeutic options for diseases with liver failure. Hepatocyte turnover is low in the adult healthy liver, but in case of injury, hepatocytes vigorously replicate and proliferate to recover the liver mass. When hepatocyte function is impaired, then a reservoir of liver progenitor cells (LPC) activates and expands. The origin of those LPC remains unclear. However, LPC are believed to have the bipotential capacity to generate hepatocytes or biliary cells depending on the nature of the cellular damage in order to restore the hepatic cell loss and function. Although such bipotentiality has been greatly demonstrated in in vitro and ex vitro studies, there is a lack of evidence regarding to whether that differentiation process occurs in vivo. Using in vivo genetic lineage tracing experiments, here we demonstrate that LPC originate from the embryonic ductal plate cells, and that they are able to generate functional hepatocytes in a mouse model of chronic liver injury. We show for the first time that in specific conditions of liver injury, the liver progenitor cell compartment proliferates and gives rise to new mature hepatocytes. In addition, we confirm that hepatocytes are responsible for the maintenance of normal liver homeostasis and for the recovery of the liver mass after acute liver injury induced by physical insult or chemical toxicity. Likewise, hepatocytes mediate hepatic regeneration in drugs (paracetamol), chemicals and toxins-induced chronic liver injury. Furthermore, we demonstrate that the LPC’s plasticity towards the hepatocytic or biliary lineage is modulated by and dependent on the microenvironment, in particular, extracellular matrix, laminin of the basement membrane and Kupffer cells (the resident liver macrophages). In conclusion, our findings indicate that in certain circumstances LPC participate to liver regeneration and wound healing by generating functional hepatocytes, and that stimulation of the differentiation process is feasible by controlling their niche. Therefore, this opens new ways to improve functional liver recovery and the outcome of patients suffering from liver failure.