Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells
Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells
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DOI：
10.1016/j.jhep.2007.07.032
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发表时间：
2008-01-01
影响因子：
25.7
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Yang, Liu;Wang, Ying;Diehl, Anna Mae
背景/目的：在肝损伤期间释放的因子，例如血小板衍生生长因子-BB（PDGF），促进肌纤维母细胞肝星状细胞（MFB）的积累，其驱动肝硬化的发病机制。Hedgehog（Hh）通路调节其他受损组织的重塑。本研究评估了自分泌产生Sonic hedgehog（Shh）促进MFB生长的假设。方法：在不加或加PDGF（一种PDGF调节激酶的药理学抑制剂）、表达激活或显性负性AKT的腺病毒或Hh信号传导抑制剂的情况下处理原代大鼠肝星状细胞（HSC）。Shh的产生，Hh抑制剂和靶基因的表达，以及HSC的生长进行了assessed.Results：HSC表达Shh，Hh通路成分，Hh抑制剂，Hip。在培养过程中，Hip表达下降，Shh产量增加，并诱导Hh靶基因表达。中和Shh抗体促进细胞凋亡。加入PDGF增加Shh表达和MFB生长。这两个过程都遵循AKT的激活，并被AKT抑制剂废除。腺病毒递送激活的AKT上调Shh表达，证明AKT在调节Shh表达中的直接作用。Shh中和抗体和其他Hh通路抑制剂阻断了PDGF.Conclusions的促有丝分裂作用：这些结果确定Shh作为MFB的自分泌生长因子，并建议Hh信号在肝硬化的发病机制中的作用。(c)2007年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Factors released during liver injury, such as platelet derived growth factor-BB (PDGF), promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth.Methods: Primary rat hepatic stellate cells (HSC) were treated without or with PDGF, a pharmacologic inhibitor of PDGF-regulated kinases, adenovirus expressing activated or dominant negative AKT, or Hh signaling inhibitors. Shh production, expression of Hh inhibitors and target genes, and HSC growth were assessed.Results: HSC expressed Shh, Hh pathway components, and the Hh inhibitor, Hip. During culture Hip expression fell, Shh production increased, and Hh target gene expression was induced. Neutralizing Shh antibodies promoted apoptosis. Adding PDGF increased Shh expression and MFB growth. Both processes followed activation of AKT and were abrogated by AKT inhibitors. Adenoviral delivery of activated AKT up-regulated Shh expression, demonstrating a direct role for AKT in regulating Shh expression. Shh-neutralizing antibodies and other Hh pathway inhibitors blocked the mitogenic effects of PDGF.Conclusions: These results identify Shh as an autocrine growth factor for MFB and suggest a role for Hh signaling in the pathogenesis of cirrhosis. (c) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.