Abstract
B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.
Highlights
The liver is a unique organ with the ability to completely regenerate to the original size after massive loss
[1] The orchestrated complex process involves a cytokine, growth factor, and metabolic network [2], among which the cytokine network is initiated through the binding of tumor necrosis factor (TNF) to TNF receptor 1 (TNFR1), which leads to the activation of nuclear factor (NF)-κB in nonparenchymal cells, the production of interleukin (IL)-6, and the activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes [2]
Angiogenesis is essential for successful liver regeneration. [4,5,6,7] Mutual growth-regulatory signaling interactions between hepatocytes and endothelial cells during liver regeneration after 70% partial hepatectomy involve vascular endothelial growth factor (VEGF), IL-6, transforming growth factor (TGF) α, fibroblast growth factor (FGF) 1, and hepatocyte growth factor (HGF) [5]
Summary
The liver is a unique organ with the ability to completely regenerate to the original size after massive loss. Seventy percent partial hepatectomy is the standard model for studying normal liver regeneration. Restoration of liver mass involves the proliferation of hepatocytes and nonparenchymal cells. [4,5,6,7] Mutual growth-regulatory signaling interactions between hepatocytes and endothelial cells during liver regeneration after 70% partial hepatectomy involve vascular endothelial growth factor (VEGF), IL-6, transforming growth factor (TGF) α, fibroblast growth factor (FGF) 1, and hepatocyte growth factor (HGF) [5]. The role of BAFF in liver regeneration has not yet been fully elucidated. We hypothesize that BAFF might play a role in liver regeneration after 70% partial hepatectomy. We investigated the role of BAFF in liver regeneration. Our findings provided important insights into the role of BAFF in angiogenesis and liver regeneration
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