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.

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.

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.

Based on studies of Foxl1-Cre;Rosa^YFP/iDTR mice, Foxl1⁺ HPCs and/or their descendants are required for the development of cholangiocytes and hepatocytes in liver after CDE diet-induced injury.