Platelet-induced cell signaling during liver regeneration

Abstract

Objective

To investigate the mechanisms driving the interaction of platelets with liver sinusoidal endothelial cells (LSEC) during liver regeneration.

Methods

Platelets were tracked in vivo in mice by intravital confocal microscopy after partial hepatectomy. In vitro, we isolated highly pure mouse LSEC and analyzed their interactions with platelets, hepatic stellate cells (HSC), Kupffer cells and hepatocytes.

Results

Recruited platelets adhered to LSEC in vivo within the remnant liver segments following partial hepatectomy and were necessary for the interleukin 6 (IL-6) burst that occurred afterwards. In vitro, platelets were activated after incubation with LSEC and released transforming growth factor β1 (TGF-β1), which stimulated LSEC to secrete IL-6 (fold increase of 9.8±0.73 relative to baseline). Antibody-mediated neutralization of TGF-B1 or its downstream SMAD signalling pathway prevented the effects of activated platelets on LSEC.

We also demonstrated that IL-6 released by LSEC stimulates HSC to produce hepatocyte growth factor (HGF) a main mitogen for hepatocytes.

Conclusion

Our results suggest that after hepatectomy, platelets initiate liver regeneration by interacting with LSEC and stimulate IL-6 release, which in turn stimulates HSC to produce HGF.