The Transforming Growth Factor-Beta (TGF-β) Mediates Acquisition of a Mesenchymal Stem Cell-Like Phenotype in Human Liver Cells
The Transforming Growth Factor-Beta (TGF-β) Mediates Acquisition of a Mesenchymal Stem Cell-Like Phenotype in Human Liver Cells
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DOI：
10.1002/jcp.22439
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发表时间：
2011-05-01
影响因子：
5.6
通讯作者：
Fabregat, Isabel
中科院分区：
文献类型：
--
作者：
Caja, Laia;Bertran, Esther;Fabregat, Isabel
转化生长因子-β (TGF-β) 在上皮细胞中介导多种有时相反的作用，诱导生长抑制和细胞凋亡，但也促进上皮间质转化 (EMT) 过程，从而增强细胞迁移和侵袭。 TGF-β 在不同的肝脏病理中发挥相关作用；然而，人们对其在人原代肝细胞中的特定信号传导和细胞效应知之甚少。在这里，我们发现 TGF-β 在人胎儿肝细胞 (HFH) 的原代培养物中抑制增殖并诱导促凋亡基因（例如 BMF 或 BIM），但也上调抗凋亡基因，例如 BCL-XL 和 XIAP。使用吉非替尼抑制表皮生长因子受体（EGFR），可以消除抗凋亡基因表达的增加，并显着增强细胞死亡。同时，TGF-β 能够在 HFH 中诱导 EMT 过程，与 Snail 上调和 E-钙粘蛋白水平降低、细胞显示间充质蛋白以及应力纤维中肌动蛋白细胞骨架的重组同时发生。有趣的是，这些细胞表现出特定肝基因表达的丧失和干细胞标记物表达的增加。使用TGF-β进行长期治疗可以选择具有去分化表型的间充质细胞群，这让人想起类祖细胞。该过程是可逆的，间充质干细胞样细胞在受控实验条件下重新分化为肝细胞。总之，我们首次证明人类肝细胞可能对 TGF-β 产生反应，诱导不同的信号，其中一些可能有助于肿瘤抑制（生长抑制和细胞凋亡），但其他信号可能介导肝肿瘤进展和侵袭（EMT 和获得干样表型）。 J.细胞。生理学。 226: 1214-1223, 2011。(C) 2010 Wiley-Liss, Inc.
Transforming growth factor-beta (TGF-beta) mediates several and sometime opposite effects in epithelial cells, inducing growth inhibition, and apoptosis but also promoting an epithelial to mesenchymal transition (EMT) process, which enhances cell migration and invasion. TGF-beta plays relevant roles in different liver pathologies; however, very few is known about its specific signaling and cellular effects in human primary hepatocytes. Here we show that TGF-beta inhibits proliferation and induces pro-apoptotic genes (such as BMF or BIM) in primary cultures of human fetal hepatocytes (HFH), but also up-regulates anti-apoptotic genes, such as BCL-XL and XIAP. Inhibition of the epidermal growth factor receptor (EGFR), using gefitinib, abrogates the increase in the expression of the anti-apoptotic genes and significantly enhances cell death. Simultaneously, TGF-beta is able to induce an EMT process in HFH, coincident with Snail up-regulation and a decrease in E-cadherin levels, cells showing mesenchymal proteins and reorganization of the actin cytoskeleton in stress fibers. Interestingly, these cells show loss of expression of specific hepatic genes and increased expression of stem cell markers. Chronic treatment with TGF-beta allows selection of a population of mesenchymal cells with a de-differentiated phenotype, reminiscent of progenitor-like cells. Process is reversible and the mesenchymal stem-like cells re-differentiate to hepatocytes under controlled experimental conditions. In summary, we show for the first time that human hepatocytes may respond to TGF-beta inducing different signals, some of them might contribute to tumor suppression (growth inhibition and apoptosis), but others should mediate liver tumor progression and invasion (EMT and acquisition of a stem-like phenotype). J. Cell. Physiol. 226: 1214-1223, 2011. (C) 2010 Wiley-Liss, Inc.