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Despite the well-known hepatoprotective role of the epidermal growth factor receptor (EGFR) pathway upon acute damage, its specific actions during chronic liver disease, particularly cholestatic injury, remain ambiguous and unresolved. Here, we analyzed the consequences of inactivating EGFR signaling in the liver on the regenerative response following cholestatic injury. For that, transgenic mice overexpressing a dominant negative mutant human EGFR lacking tyrosine kinase activity (ΔEGFR) in albumin-positive cells were submitted to liver damage induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), an experimental model resembling human primary sclerosing cholangitis. Our results show an early activation of EGFR after 1-2 days of a DDC-supplemented diet, followed by a signaling switch-off. Furthermore, ΔEGFR mice showed less liver damage and a more efficient regeneration following DDC injury. Analysis of the mechanisms driving this effect revealed an enhanced activation of mitogenic/survival signals, AKT and ERK1/2-MAPKs, and changes in cell turnover consistent with a quicker resolution of damage in response to DDC. These changes were concomitant with profound differences in the profile of intrahepatic immune cells, consisting of a shift in the M1/M2 balance towards M2 polarity, and the Cd4/Cd8 ratio in favor of Cd4 lymphocytes, overall supporting an immune cell switch into a pro-restorative phenotype. Interestingly, ΔEGFR livers also displayed an amplified ductular reaction, with increased expression of EPCAM and an increased number of CK19-positive ductular structures in portal areas, demonstrating an overexpansion of ductular progenitor cells. In summary, our work supports the notion that hepatocyte-specific EGFR activity acts as a key player in the crosstalk between parenchymal and non-parenchymal hepatic cells, promoting the pro-inflammatory response activated during cholestatic injury and therefore contributing to the pathogenesis of cholestatic liver disease. © 2022 The Pathological Society of Great Britain and Ireland., (© 2022 The Pathological Society of Great Britain and Ireland.)

Oval cells (OCs) is the name of hepatic progenitor cells (HPCs) in rodents. They are a small population of cells in the liver with the remarkable ability to proliferate and regenerate hepatocytes and cholangiocytes in response to acute liver damage. Isolating OCs generally requires a pretreatment with special diets, chemicals, and/or surgery to induce hepatic damage and OC proliferation in mice. Unfortunately, these pretreatments are not only painful for the mice but also increase the cost of the assays, and the effects on the different organs as well as on various liver cells are still unclear. Therefore, the search for a protocol to obtain OCs without prior liver damage is mandatory. In our study, we present a protocol to isolate murine OCs from healthy liver (HL-OCs) and compare them with OCs isolated from mice pretreated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC-OCs). Our results demonstrated that cells derived from untreated mice exhibited similar behavior to those from treated mice in terms of surface marker expression, proliferation, and differentiation capacity. Therefore, given the impracticability of isolating human cells with prior hepatotoxic treatment, our model holds promise for enabling the isolation of progenitor cells from human tissue in the future. This advancement could prove invaluable for translational medicine in the understanding and treatment of liver diseases. [ABSTRACT FROM AUTHOR]