TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure.
TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure.
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DOI：
10.1371/journal.pone.0167158
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Amicone L
中科院分区：
文献类型：
--
作者：
De Santis Puzzonia M;Cozzolino AM;Grassi G;Bisceglia F;Strippoli R;Guarguaglini G;Citarella F;Sacchetti B;Tripodi M;Marchetti A;Amicone L
在所有哺乳动物中，成年肝脏均显示双核和单核多倍体肝细胞。肝脏多倍化在出生后开始，伴随着广泛的肝细胞双核，并产生多个倍性类别的肝细胞。虽然肝细胞多倍体的功能意义变得越来越清楚，但它是如何触发和维持的仍需要澄清。本研究的目的是确定肝细胞双核/多倍化的主要诱导剂以及所涉及的细胞和分子机制。我们发现，在分析的几种已知参与早期肝脏发育和/或质量控制的细胞因子中，TGFbeta1能够诱导培养物中肝细胞的双核以及预期的形态变化。最重要的是，在健康小鼠断奶期间，当生理性双核发生时，药物抑制TGFbeta信号传导，导致肝细胞双核率显着降低，而不影响细胞增殖和肝指数。通过视频显微镜评估，TGFβ诱导的肝细胞双核是由胞质分裂失败引起的，并且与分裂细胞中体的胞质分裂调节剂 RhoA-GTPase 的离域有关。特定化学抑制剂的使用证明观察到的事件是 Src 依赖性的。最后，通过 TGFbeta 撤除完全恢复上皮表型，产生能够维持多倍体状态的细胞后代。总之，我们确定 TGFbeta 是体外和体内肝细胞双核的主要诱导剂，从而赋予这种多效性细胞因子新的作用。双核/四倍体肝细胞的产生是由于分子轴 TGFbeta/Src/RhoA 控制的胞质分裂失败。
In all mammals, the adult liver shows binucleated as well as mononucleated polyploid hepatocytes. The hepatic polyploidization starts after birth with an extensive hepatocyte binucleation and generates hepatocytes of several ploidy classes. While the functional significance of hepatocyte polyploidy is becoming clearer, how it is triggered and maintained needs to be clarified. Aim of this study was to identify a major inducer of hepatocyte binucleation/polyploidization and the cellular and molecular mechanisms involved. We found that, among several cytokines analyzed, known to be involved in early liver development and/or mass control, TGFbeta1 was capable to induce, together with the expected morphological changes, binucleation in hepatocytes in culture. Most importantly, the pharmacological inhibition of TGFbeta signaling in healthy mice during weaning, when the physiological binucleation occurs, induced a significant decrease of hepatocyte binucleation rate, without affecting cell proliferation and hepatic index. The TGFbeta-induced hepatocyte binucleation resulted from a cytokinesis failure, as assessed by video microscopy, and is associated with a delocalization of the cytokinesis regulator RhoA-GTPase from the mid-body of dividing cells. The use of specific chemical inhibitors demonstrated that the observed events are Src-dependent. Finally, the restoration of a fully epithelial phenotype by TGFbeta withdrawal gave rise to a cell progeny capable to maintain the polyploid state. In conclusion, we identified TGFbeta as a major inducer of hepatocyte binucleation both in vitro and in vivo, thus ascribing a novel role to this pleiotropic cytokine. The production of binucleated/tetraploid hepatocytes is due to a cytokinesis failure controlled by the molecular axis TGFbeta/Src/RhoA.
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影响因子：
13.5
作者：
Bordoni, V;Alonzi, T;Tripodi, M
通讯作者：
Tripodi, M
影响因子：
4.3
作者：
Cozzolino AM;Noce V;Battistelli C;Marchetti A;Grassi G;Cicchini C;Tripodi M;Amicone L
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Amicone L
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作者：
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DOI：
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发表时间：
2012-06-01
影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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