Intact signaling by transforming growth factor β is not required for termination of liver regeneration in mice
Intact signaling by transforming growth factor β is not required for termination of liver regeneration in mice
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DOI：
10.1002/hep.20426
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发表时间：
2004-11-01
期刊：
影响因子：
13.5
通讯作者：
Thorgeirsson, SS
中科院分区：
文献类型：
--
作者：
Oe, S;Lemmer, ER;Thorgeirsson, SS
转化生长因子β（TGF-β）是体外肝细胞增殖的有效抑制剂，并且被认为是肝脏生长的关键负调节剂。为了直接阐明TGF-β信号传导在体内肝再生中的作用，通过将“floxed”Tgfbr 2条件性敲除小鼠与在白蛋白启动子控制下表达Cre的转基因小鼠杂交，在肝细胞中选择性地缺失TGF-β II型受体基因（Tgfbr 2）。从肝脏特异性Tgfbr 2基因敲除（R2 LivKO）小鼠中分离的肝细胞对TGF-β 1的生长抑制作用不敏感。70%部分肝切除术后的DNA合成高峰出现较早（36小时与48小时），R2 LivKO小鼠的DNA合成高峰是对照组的1.7倍。增殖的R2 LivKO肝细胞加速进入S期与Rb蛋白的过度磷酸化和细胞周期蛋白D1和细胞周期蛋白E的早期上调相一致。然而，到部分肝切除术后120小时，对照和R2 LivKO肝脏中的肝细胞增殖均恢复至基线。再生的R2 LivKO肝脏显示激活素A信号传导增加和Smad途径的持续活性的证据。通过特异性抑制剂卵泡抑素阻断激活素A信号传导导致在120小时时肝细胞增殖增加，特别是在R2 LivKO肝脏中。总之，TGF-β调节肝细胞的G（1）到S相转变，但TGF-β的完整信号传导并不是肝再生终止所必需的。当通过TGF-β途径的信号传导被消除时，激活素A增加的信号传导可以补偿以调节肝再生，并且可能是肝再生终止的主要因素。
Transforming growth factor beta (TGF-beta) is a potent inhibitor of hepatocyte proliferation in vitro and is suggested to be a key negative regulator of liver growth. To directly address the role of TGF-beta signaling in liver regeneration in vivo, the TGF-beta type II receptor gene (Tgfbr2) was selectively deleted in hepatocytes by crossing "floxed" Tgfbr2 conditional knockout mice with transgenic mice expressing Cre under control of the albumin promoter. Hepatocytes isolated from liver-specific Tgfbr2 knockout (R2LivKO) mice were refractory to the growth inhibitory effects of TGF-beta1. The peak of DNA synthesis after 70% partial hepatectomy occurred earlier (36 vs. 48 hours) and was 1.7-fold higher in R2LivKO mice compared with controls. Accelerated S-phase entry by proliferating R2LivKO hepatocytes coincided with the hyperphosphorylation of Rb protein and the early upregulation of cyclin D1 and cyclin E. However, by 120 hours after partial hepatectomy, hepatocyte proliferation was back to baseline in both control and R2LivKO liver. Regenerating R2LivKO liver showed evidence of increased signaling by activin A and persistent activity of the Smad pathway. Blockage of activin A signaling by the specific inhibitor follistatin resulted in increased hepatocyte proliferation at 120 hours, particularly in R2LivKO livers. In conclusion, TGF-beta regulates G(1) to S phase transition of hepatocytes, but intact signaling by TGF-beta is not required for termination of liver regeneration. Increased signaling by activin A may compensate to regulate liver regeneration when signaling through the TGF-beta pathway is abolished, and may be a principal factor in the termination of liver regeneration.