Cicchini Carla, Amicone Laura, Alonzi Tonino, Marchetti Alessandra, Mancone Carmine, Tripodi Marco
Istituto Pasteur-Fondazione Cenci Bolognetti, Department of Cellular Biotechnologies and Haematology, Sapienza University of Rome, Rome, Italy.
Liver Int. 2015 Feb;35(2):302-10. doi: 10.1111/liv.12577. Epub 2014 May 20.
The complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells. Only within a correct tissue organization, in fact, they stably maintain their identity and differentiated phenotype. The loss of histotype identity, which invariably occurs in the primary hepatocytes in culture, or in vivo in particular pathological conditions (fibrosis and tumours), is mainly because of the phenomenon of epithelial-to-mesenchymal transition (EMT). The EMT process, that occurs in the many epithelial cells, appears to be driven by a number of general, non-tissue-specific, master transcriptional regulators. The reverse process, the mesenchymal-to-epithelial transition (MET), as yet much less characterized at a molecular level, restores specific epithelial identities, and thus must include tissue-specific master elements. In this review, we will summarize the so far unveiled events of EMT/MET occurring in liver cells. In particular, we will focus on hepatocyte and describe the pivotal role in the control of EMT/MET dynamics exerted by a tissue-specific molecular mini-circuitry. Recent evidence, indeed, highlighted as two transcriptional factors, the master gene of EMT Snail, and the master gene of hepatocyte differentiation HNF4α, exhorting a direct reciprocal repression, act as pivotal elements in determining opposite cellular outcomes. The different balances between these two master regulators, further integrated by specific microRNAs, in fact, were found responsible for the EMT/METs dynamics as well as for the preservation of both hepatocyte and stem/precursor cells identity and differentiation. Overall, these findings impact the maintenance of stem cells and differentiated cells both in in vivo EMT/MET physio-pathological processes as well as in culture.
肝脏不同组织类型之间复杂的空间和旁分泌关系对于肝实质细胞的正常功能至关重要。事实上，只有在正确的组织架构中，它们才能稳定地维持自身特性和分化表型。组织类型特性的丧失，在体外培养的原代肝细胞中总是会发生，或者在体内特定病理状况（纤维化和肿瘤）下发生，主要是由于上皮-间质转化（EMT）现象。EMT过程发生在许多上皮细胞中，似乎由一些通用的、非组织特异性的主要转录调节因子驱动。相反的过程，即间质-上皮转化（MET），在分子水平上的特征还少得多，它能恢复特定的上皮特性，因此必须包括组织特异性的主要元件。在本综述中，我们将总结目前在肝细胞中发现的EMT/MET事件。特别地，我们将聚焦于肝细胞，并描述由一个组织特异性分子微回路在控制EMT/MET动态变化中所起的关键作用。事实上，最近的证据表明，两个转录因子，即EMT的主要基因Snail和肝细胞分化的主要基因HNF4α，相互直接抑制，在决定相反的细胞结局中起关键作用。实际上，这两个主要调节因子之间的不同平衡，再由特定的微小RNA进一步整合，被发现是EMT/MET动态变化以及肝细胞和干细胞/前体细胞特性及分化维持的原因。总体而言，这些发现影响了体内EMT/MET生理病理过程以及培养过程中干细胞和分化细胞的维持。
