Ablation of Foxl1-Cre-Labeled Hepatic Progenitor Cells and Their Descendants Impairs Recovery of Mice From Liver Injury

作者：Shin Soona; Upadhyay Naman; Greenbaum Linda E; Kaestner Klaus H^*

来源：Gastroenterology, 2015, 148(1): 192-U670.

DOI：10.1053/j.gastro.2014.09.039

• HPCs
• Oval Cells
• Mouse Model
• Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS: Foxl1(+) hepatic progenitor cells (HPCs) differentiate into cholangiocytes and hepatocytes after liver injury. We investigated the requirement for Foxl1(+) HPCs in recovery from liver injury in mice. METHODS: We developed mice in which we could trace and delete Foxl1-expressing HPCs and their descendants (Foxl1-Cre;Rosa(YFP/iDTR)-inducible diphtheria toxin receptor [iDTR] mice). Foxl1-Cre-negative mice were used as controls. Liver damage was induced in male mice by placing them on choline-deficient, ethionine-supplemented (CDE) diets for 15 days; mice then were placed on normal diets and allowed to recover. Liver damage was induced in female mice by placing them on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diets, followed by a recovery period. Some mice were given injections of diphtheria toxin during the recovery phase to delete Foxl1-Cre-marked HPCs and their descendants. Livers were collected from all mice and analyzed by immunofluorescence, quantitative reverse-transcription polymerase chain reaction, flow cytometry, and histologic analyses. RESULTS: Foxl1-Cre-marked HPCs were required for the development of cholangiocytes and hepatocytes in livers after CDE diet-induced injury. A smaller percentage of yellow fluorescent protein-positive (YFP+) hepatocytes contained markers of oxidative stress, DNA damage, or cell death than YFP-negative hepatocytes, indicating that YFP+ hepatocytes are newly formed cells. Injection of diphtheria toxin deleted YFP+ cells from Foxl1-Cre;Rosa(YFP/iDTR) mice and prevented the resolution of hepatic steatosis. In mice recovering from DDC diet-induced injury, most cholangiocytes arose from Foxl1-Cre-marked HPCs. Deletion of YFP+ cells did not alter levels of markers of liver injury or liver function. CONCLUSIONS: Based on studies of Foxl1-Cre; RosaYFP/iDTR mice, Foxl1(+) HPCs and/or their descendants are required for the development of cholangiocytes and hepatocytes in liver after CDE diet-induced injury.

• 出版日期2015-1