Bone marrow-derived c-jun N-terminal kinase-1 (JNK1) mediates liver regeneration

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Liver regeneration is controlled by a complex network of signaling molecules, and a prominent role for c-jun N-terminal kinase has been suggested during this process. In the present study, we aimed to characterize and define the cell-type-specific contribution of JNK1 activation during liver regeneration. We used hepatocyte-specific JNK1 knockout mice (JNK1Δhepa) using the cre/lox-P system. We performed partial hepatectomy (PH) in WT, JNK1Δhepa and JNK1−/− animals and investigated time-points up to 72h after PH. Additionally, bone marrow transplantation experiments were conducted in order to identify the contribution of hematopoietic cell-derived JNK1 activation for liver regeneration. Our results show that liver regeneration was significantly impaired in JNK1−/− compared to JNK1Δhepa and WT animals. These data were evidenced by lower BrdU incorporation and decreased cell cycle markers such as Cyclin A, Cyclin D, E2F1 and PCNA 48h after PH in JNK1−/− compared with JNK1Δhepa and WT livers. In JNK1−/− mice, our findings were associated with a reduced acute phase response as evidenced by a lower activation of the IL-6/STAT3/SAA-1 cascade. Additionally, CD11b+Ly6G+-cells were decreased in JNK1−/− compared with JNK1Δhepa and WT animals after PH. The transplantation of bone marrow-derived JNK1−/− into WT recipients caused significant reduction in liver regeneration. Interestingly, the transplantation of JNK1−/− into mice lacking JNK1 in hepatocytes only partially delayed liver regeneration. In summary, we provide evidence that (1) JNK1 in hematopoietic cells is crucial for liver regeneration, and (2) a synergistic function between JNK1 in hepatocytes and hematopoietic-derived cells is involved in the hepatic regenerative response.