Liver is unique in its capacity to regenerate in response to

Liver is unique in its capacity to regenerate in response to injury or tissue loss. permit subsequent hepatoblast differentiation. In the same line, the Wnt family and -catenin/T-cell factor pathway is clearly involved in the maintenance of liver stemness phenotype, and its repression is necessary for liver differentiation during development. Collectively, data indicate that liver stem/progenitor cells follow their own rules and regulations. The same signals that are essential for their activation, expansion and differentiation Runx2 are good candidates to contribute, under adequate conditions, to the paradigm of transformation from a pro-regenerative to a pro-tumorigenic role. From a clinical perspective, Brivanib this is a fundamental issue for liver stem/progenitor cell-based therapies. infusion of Brivanib a combination of HGF and EGF enhance the mitogenic response of Brivanib oval cells after administration of 2-acetylaminofluorene[10], which reveals the relevance of both growth factors in liver stem/progenitor cell biology. Additionally, different studies have revealed that oval cells also respond to other growth factors in an autocrine/paracrine manner[11]. The transforming growth factor (TGF)- family of cytokines play a relevant role in the maintenance of embryonic stem cell identity, and it has been shown that the specification of pancreas and liver progenitors is restricted by the TGF- pathway[12]. All these growth factors and cytokines might modulate not only proliferation of liver stem/progenitor cells, but also cell death, as well as contributing to their terminal differentiation. This review gives an update on recent relevant studies of the growth factors and cytokine-driven intracellular pathways that govern liver stem/progenitor cell expansion and differentiation, and the relevance of these signals in liver development, regeneration and carcinogenesis. TYROSINE KINASE RECEPTOR-MEDIATED SIGNALING PATHWAYS HGF HGF was firstly identified in the 1980s as a potent mitogen for hepatocytes[13-15]. A factor secreted by fibroblasts and smooth muscle cells was discover separately, which promoted epithelial cell scattering[16]. Later studies unraveled that HGF and scatter factor were indistinguishable[17,18]. HGF is a growth factor that induces a wide range of biological activities, including stimulation of proliferation, migration, morphogenesis, and survival of a variety of cell types[19-24], which plays a major role in tissue formation and homeostasis. HGF acts through binding to its tyrosine kinase receptor, Met. Ligand-receptor binding results in autophosphorylation of the receptor in specific tyrosine residues located in the C-terminal domain, and subsequent phosphorylation/activation of multiple adapter and signal transducing proteins, such as growth factor receptor-bound protein 2 (Grb2)/Sos, Ras-mitogen-activated protein kinase, Grb2-associated binding protein 1 (Gab1), phosphoinositide 3-kinase (PI3K), phospholipase C-, p38, and signal transducer and activator of transcription (STAT)-3, among others, which mediate the biological activities of HGF/c-Met[25,26]. For decades, HGF has been recognized as a growth factor involved in the hepatocyte proliferative response during liver regeneration (a recent review on the role of HGF in liver regeneration can be found in[3]), but an unequivocal demonstration of an essential role of the HGF/c-Met signaling in liver regeneration has only been provided recently. Thus, liver specific c-Met and HGF conditional knock-out mice show an impairment of the regenerative response[27-29]. Hepatocytes that lack a functional c-Met display reduced basal survival and Brivanib a higher sensitivity to Fas-induced liver damage, both and infusion of HGF during AAF/PH-induced liver regeneration stimulates oval cell expansion into the liver lobules[10]. Similar results have been obtained by transfer of HGF cDNA into liver subjected to the Solt-Farber regime[42]. HGF-dependent mitogenic activity has also been shown in rat and mouse oval cell lines by either adenovirus-mediated transfer of the HGF gene or addition of exogenous HGF[43-46]. The molecular mechanisms that mediate the mitogenic effects of HGF in liver progenitors appear to be cell-type specific, because PI3K/AKT activation[43] and nuclear factor-B activation, downstream of p38 and extracellular signal-regulated kinase (ERK) MAPKs[44], are involved. Additionally, bi-potential hepatoblast cell lines (precursors of both hepatocytes and cholangiocytes) have been established from transgenic animals expressing a constitutively active human Met[47]. However, HGF Brivanib is much more than a mitogen for liver stem/progenitor cells. HGF effectively protects WB-F344 cell from apoptosis induced by tumor necrosis factor- in a dose-dependent manner[44]. More recently, using a novel model of genetically modified oval cells that harbor an inactivated Met tyrosine kinase, we have demonstrated that loss of Met increases sensitivity to apoptosis caused by serum deprivation or treatment with TGF-[46]. By virtue of these results, we hypothesize that Met-driven anti-apoptotic activity plays an important role supporting the expansion of liver progenitors following liver injury, by helping them to overcome the local tissue injuries and inhibitory signals. Therefore, the HGF/c-Met.

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