肝损伤
癌症研究
肝再生
肝细胞
祖细胞
表皮生长因子受体
蛋白激酶B
再生(生物学)
表皮生长因子受体抑制剂
信号转导
医学
生物
细胞生物学
免疫学
受体
内科学
干细胞
生物化学
体外
作者
Nerea Lazcanoiturburu,Juan García‐Sáez,Carlos González‐Corralejo,César Roncero,Julián Sanz,Carlos Martín‐Rodríguez,M. Pilar Valdecantos,Adoración Martínez‐Palacián,Laura Almalé,Paloma Bragado,Silvia Calero‐Pérez,Almudena Fernández,María García‐Bravo,Carmen Guerra,Lluı́s Montoliu,José C. Segovia,Ángela M. Valverde,Isabel Fabregat,Blanca Herrera,Aránzazu Sánchez
摘要
Abstract 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.
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