Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.
Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.
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作者：
在慢性损伤期间，成年肝脏的再生能力受损。在此情况下，双潜能肝祖细胞（HPCs）被激活，并且能够再生胆管细胞和肝细胞。肝脏个体发育过程中的Notch和Wnt信号通路已有描述，但它们在肝祖细胞介导的肝脏再生中的作用尚不清楚。在此，我们通过人类患病肝脏以及具有胆管和肝细胞再生的小鼠胆管反应模型表明，Notch和Wnt信号通路在激活的肌成纤维细胞和巨噬细胞构成的肝祖细胞微环境中指导肝祖细胞的分化。在胆管再生过程中，肝祖细胞中的Numb表达下调，Jagged1促进肝祖细胞向胆管细胞分化。在肝细胞再生过程中，巨噬细胞衍生的经典Wnt信号通路维持肝祖细胞中Numb的表达，并且Notch信号通路减弱，促进肝细胞分化。这种占主导的Wnt状态是通过微环境中的巨噬细胞吞噬肝细胞碎片而被刺激产生的，并且能够直接影响肝祖细胞。反过来，巨噬细胞Wnt3a的表达促进肝细胞再生——从而例证了成年实质器官再生中的一种新的正反馈机制。
During chronic injury, regeneration of the adult liver becomes impaired. In this context bipotent Hepatic Progenitor Cells (HPCs) become activated and can regenerate both cholangiocytes and hepatocytes. Notch and Wnt signalling during hepatic ontogeny are described, but their roles in HPC mediated liver regeneration are unclear. Here we show in human diseased liver and murine models of the ductular reaction with biliary and hepatocyte regeneration that Notch and Wnt signalling direct HPC specification within the activated myofibroblasts and macrophages HPC niche. During biliary regeneration, Numb is downregulated in HPCs, Jagged1 promotes biliary specification within HPCs. During hepatocyte regeneration, macrophage derived canonical Wnt signalling maintains Numb within HPCs, and Notch signalling is reduced promoting hepatocyte specification. This dominant Wnt state is stimulated through engulfment of hepatocyte debris by niche macrophages and can directly influence the HPCs. Macrophage Wnt3a expression in turn facilitates hepatocyte regeneration – thus exemplifying a novel positive feedback mechanism in adult parenchymal regeneration.
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影响因子：
4.6
作者：
Hofmann, Jennifer J.;Zovein, Ann C.;Iruela-Arispe, M. Luisa
通讯作者：
Iruela-Arispe, M. Luisa
DOI：
10.1016/j.biocel.2010.10.015
发表时间：
2011-02
影响因子：
4
作者：
Choi, Steve S.;Omenetti, Alessia;Syn, Wing-Kin;Diehl, Anna Mae
通讯作者：
Diehl, Anna Mae
影响因子：
13.5
作者：
Crosnier, C;Attié-Bitach, T;Vekemans, M
通讯作者：
Vekemans, M
影响因子：
30.8
作者：
Li, LH;Krantz, ID;Spinner, NB
通讯作者：
Spinner, NB
影响因子：
6
作者：
Fickert, Peter;Stoeger, Ulrike;Trauner, Michael
通讯作者：
Trauner, Michael