Functional significance of ductular reactions in liver disease

• Applicant: Privatdozent Dr. Fabian K. Geisler
• Subject Area: Gastroenterology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 387228542

The liver has a unique capacity to regenerate. In virtually all forms of liver injury, ductular reactions (DRs) emerge, which comprise cellular reactions of ductular (biliary) phenotype at the portal-parenchymal interface. It is widely believed that ductular reactive cells (DRCs) comprise a transit-amplifying cellular progeny of adult facultative liver stem cells located in the outermost terminals of the biliary tree, the canals of Hering. Mainly derived from 2D histological and in vitro studies, it has been widely accepted as a basic principle of liver repair that these DRCs act as bipotential progenitors and serve as an adult cellular emergency compartment. They are believed to be capable of producing both cholangiocytes and hepatocytes in case acute or chronic liver injury compromise self-duplication of these epithelial cells. Hence, DRCs are frequently synonymously denominated liver progenitor cells or adult liver stem cells. However, recent well-controlled mouse lineage tracing studies from our and other groups have put this classical concept of DRCs acting as significant hepatocyte backup pool to test. Although the final verdict remains controversial, it has become clear that DRs do not function as hepatocyte progenitors in most injury settings and therefore the physiological significance of this conserved injury response remains enigmatic.By utilizing our recently established DR-lineage tracing system in combination with 3D confocal architectural imaging, we have noticed that the canalicular-biliary linkage becomes disrupted in selected liver injury models displaying DRs. Based on our preliminary morphological data, we hypothesize that DRs may represent a general conserved mechanism among different injury patterns primarily aiming at restoring the canalicular-ductular connectivity for proper bile flow, rather than acting as bipotential progenitors. We aim at providing a comprehensive analysis of the 3D structure of DRs and their linkage to the canalicular system in injury models of multiple etiologies. By applying multicolor and dual lineage labeling strategies, advanced 3D techniques, and novel mouse models for specific ablation of the DR response (PcnaF/F mouse), we intend to unravel the physiological function of DRs in injury repair. Further, by introducing a novel mouse model mimicking liver disease with hepatocyte-specific replicative arrest, we seek to resolve the highly topical and controversial question of whether and, if so, under what conditions biliary-derived DRCs can give rise to new hepatocytes in a quantitatively relevant way. Moreover, irrespective of the capability of DRCs to act as hepatocyte progenitors, we will characterize the utility of biliary-derived DRCs for cellular therapy of inborn bile duct paucity.Our study will provide fundamental new insights into the functional significance of DRs in liver repair, which may have a wide-ranging impact on new therapeutical strategies for acute and chronic liver failure.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Maximilian Reichert