National Creative Research Initiatives Center for Cell Division and Differentiation, Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Nat Commun. 2016 Jun 30;7:11961. doi: 10.1038/ncomms11961.
The Hippo pathway regulates the self-renewal and differentiation of various adult stem cells, but its role in cell fate determination and differentiation during liver development remains unclear. Here we report that the Hippo pathway controls liver cell lineage specification and proliferation separately from Notch signalling, using mice and primary hepatoblasts with liver-specific knockout of Lats1 and Lats2 kinase, the direct upstream regulators of YAP and TAZ. During and after liver development, the activation of YAP/TAZ induced by loss of Lats1/2 forces hepatoblasts or hepatocytes to commit to the biliary epithelial cell (BEC) lineage. It increases BEC and fibroblast proliferation by up-regulating TGFβ signalling, but suppresses hepatoblast to hepatocyte differentiation by repressing Hnf4α expression. Notably, oncogenic YAP/TAZ activation in hepatocytes induces massive p53-dependent cell senescence/death. Together, our results reveal that YAP/TAZ activity levels govern liver cell differentiation and proliferation in a context-dependent manner.
Hippo 通路调节各种成体干细胞的自我更新和分化，但它在肝脏发育过程中对细胞命运决定和分化的作用尚不清楚。在这里，我们使用小鼠和具有 Lats1 和 Lats2 激酶（YAP 和 TAZ 的直接上游调节剂）肝特异性敲除的原代肝母细胞报告说，Hippo 通路独立于 Notch 信号分别控制肝细胞谱系特化和增殖。在肝脏发育过程中和之后，Lats1/2 的缺失激活的 YAP/TAZ 迫使肝母细胞或肝细胞向胆管上皮细胞 (BEC) 谱系分化。它通过上调 TGFβ 信号增加 BEC 和成纤维细胞的增殖，但通过抑制 Hnf4α 的表达抑制肝母细胞向肝细胞分化。值得注意的是，肝细胞中致癌性 YAP/TAZ 的激活诱导大量依赖 p53 的细胞衰老/死亡。总之，我们的结果表明，YAP/TAZ 的活性水平以依赖于上下文的方式控制肝细胞的分化和增殖。
