Platelets contribute to the reduction of liver fibrosis in mice

Abstract

Background and Aim: Several recent studies have reported that liver cirrhosis (LC) can be ameliorated, but few adequate strategies are available against liver fibrosis. Although LC clinically shows thrombocytopenia and hypersplenism, the correlation with liver fibrosis and platelets remains unclear. The aim of the present study was to investigate the effect of platelets on liver fibrosis in mouse models. Methods: To induce liver fibrosis, C57BL6 female mice were injected i.p. with 1 mL/kg carbon tetrachloride (CCl4) twice a week for 8 weeks. Thrombocytosis was achieved by giving thrombopoietin or splenectomy in addition to CCl4 intoxication. At 8 weeks, whole blood and liver specimens were obtained for studies as follows: peripheral platelet counts, histopathological examination, hydroxyproline assay, immunostaining, quantification of mRNA expression, and microarray analysis. Results: Thrombocytosis significantly reduced liver fibrosis and hydroxyproline content of liver tissues compared to mice with CCl4 administration alone. Platelets suppressed increments in mRNA expression for transforming growth factor‐β, and increased matrix metalloproteinase‐9 expression in the liver. Microarray analysis of the liver revealed that platelets upregulated gene expressions involved in cell proliferation compared to expression in mice with CCl4 intoxication alone. Platelets also increased liver volume, proliferative cell nuclear antigen labeling index, and mitotic index in fibrotic mice. Conclusion: These results clearly show that platelets reduce liver fibrosis and promote liver regeneration, even under cirrhotic conditions. We, therefore, propose that platelets could offer a potent tool in the treatment of liver cirrhosis.

Platelet Transfusion Improves Liver Function in Patients with Chronic Liver Disease and Cirrhosis

“…Platelets promote hepatocyte proliferation and have an anti-fibrotic effect in vitro (Matsuo et al 2008;Kawasaki et al 2010;Ikeda et al 2011), and thrombocytosis promotes liver regeneration and reduces liver fibrosis in vivo (Murata et al 2007;Murata et al 2008b;Myronovych et al 2008;Watanabe et al 2009). We hypothesized that platelet increment therapy would improve liver function in humans.…”

“…In addition, liver sinusoidal endothelial cells (LSECs), which constitute the sinusoidal wall, are involved in liver regeneration (Malik et al 2002), and platelets stimulate LSECs to promote hepatocyte proliferation (Kawasaki et al 2010). Thrombocytosis promotes liver regeneration not only in normal livers but also in fibrotic livers (Murata et al 2007;Murata et al 2008b;Myronovych et al 2008;Watanabe et al 2009). Hepatic stellate cells (HSCs) play a major role in liver fibrosis (Friedman 2008).…”

“…Hepatic stellate cells (HSCs) play a major role in liver fibrosis (Friedman 2008). Platelets suppress the activation of HSCs by releasing adenosine 5′-triphosphate (Ikeda et al 2011), and thrombocytosis reduces liver fibrosis (Murata et al 2008b;Watanabe et al 2009). Taken together, these findings indicate that platelets promote liver regeneration and reduce liver fibrosis and that platelet increment therapy may be effective for patients with CLD and cirrhosis.…”

Stable Liver Function during Long-Term Administration of Eltrombopag, a Thrombopoietin Receptor Agonist, in Patients with Chronic Liver Disease

“…We have reported that platelets could improve liver fibrosis (Murata et al 2007;Watanabe et al 2009) and accelerate liver regeneration (Matsuo et al 2008). However, platelet increment therapies, such as splenectomy and platelet transfusion, have been reported to have adverse effects, although they have ameliorating effects for CLD and cirrhosis.…”

“…Platelets promote hepatocyte proliferation (Matsuo et al 2008) and exert anti-fibrotic effects in vitro (Ikeda et al 2012), and thrombocytosis promotes liver regeneration and reduces liver fibrosis in vivo (Murata et al 2007;Watanabe et al 2009). We hypothesized that platelet transfusion therapy would improve liver function in humans (Murata et al 2007).…”