Regulation of signal transduction and role of platelets in liver regeneration

Abstract

Among all organs, the liver has a unique regeneration capability after sustaining injury or the loss of tissue that occurs mainly due to mitosis in the hepatocytes that are quiescent under normal conditions. Liver regeneration is induced through a cascade of various cytokines and growth factors, such as, tumor necrosis factor alpha, interleukin-6, hepatocyte growth factor, and insulin-like growth factor, which activate nuclear factor κB, signal transducer and activator of transcription 3, and phosphatidyl inositol 3-kinase signaling pathways. We previously reported that platelets can play important roles in liver regeneration through a direct effect on hepatocytes and collaborative effects with the nonparenchymal cells of the liver, including Kupffer cells and liver sinusoidal endothelial cells, which participate in liver regeneration through the production of various growth factors and cytokines. In this paper, the roles of platelets and nonparenchymal cells in liver regeneration, including the associated cytokines, growth factors, and signaling pathways, are described.

Figure 1

The Roles of Platelets and the Signal Transductions Identified as the Major Cascades in Hepatocyte Proliferation. After liver injury, Kupffer cells can play a crucial role in the accumulation of platelets in the liver sinusoids and the production of cytokines, such as, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα). Moreover, Kupffer cells induce the translocation of platelets into the space of Disse and the direct contact between platelets and hepatocytes, which trigger the release of growth factors, such as, hepatocyte growth factor (HGF) and insulin-like growth factor (IGF)-1, which are necessary for hepatocyte proliferation. Platelets also have direct contact with liver sinusoidal endothelial cells (LSECs), which trigger the release of sphingosine 1-phosphate (S1P). S1P induces the secretion of IL-6 from LSECs, which promotes hepatocyte proliferation. During hepatocyte proliferation, IL-6 binding induces both the dimerization and the phosphorylation of gp130 and promotes the docking site of signal transducer and activator of transcription 3 (STAT3). STAT3 is then phosphorylated and translocated to the nucleus. Phosphatidyl inositol 3-kinase (PI3K)/Akt signaling pathway is essential for the platelet-induced hepatocyte proliferation and is activated via the receptor tyrosine kinases through the stimulation of HGF, IGF, IL-6, and many other signaling molecules. Phosphorylated Akt activates glycogen synthase kinase 3β (GSK3β), which induces DNA synthesis and cellular mitosis in hepatocytes. Other downstream Akt factors including mTOR and p70^S6K also play critical roles in regulating the growth of hepatocytes. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) signaling pathway is also immediately activated after hepatectomy and thereafter phosphorylated ERK translocates to the nucleus. TNFα/nuclear factor κB (NFκB) signaling pathway is activated via the TNF receptor 1 (TNFR1). NFκB is a heterodimer composed of two subunits, p65 and p50, with inactivated by inhibitor of NFκB (IκB). After stimulation with TNFα, NFκB is activated by the removal of IκB from its p65 subunit, followed by the migration to the cell nucleus.