Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667.
During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.
在慢性损伤过程中，一群具有多能性的肝祖细胞（HPC）被激活，以再生胆管细胞和肝细胞。在这里，我们在人类疾病肝脏和小鼠胆管反应模型中表明，Notch 和 Wnt 信号通过与激活的肌成纤维细胞或巨噬细胞相互作用来指导 HPC 的特化。具体来说，我们发现，在胆管再生过程中，肌成纤维细胞表达 Jagged 1（Notch 配体）促进了 HPC 中的 Notch 信号，从而使它们特化为胆管细胞。相反，在肝细胞再生过程中，巨噬细胞吞噬肝细胞碎片诱导 Wnt3a 的表达。这导致附近 HPC 中的经典 Wnt 信号，从而维持这些细胞内 Numb（细胞命运决定因子）的表达，并促进它们向肝细胞的特化。通过这两种途径，慢性肝损伤期间的成人实质再生得到促进。
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