Platelets stimulate liver sinusoidal endothelial cells to secrete interleukin-6 during the early phase of liver regeneration in mice

In liver injury, recruitment of bone marrow (BM) progenitors of liver sinusoidal endothelial cells (sprocs) is necessary for normal liver regeneration. Hepatic vascular endothelial growth factor (VEGF) is a central regulator of the recruitment process. We examine whether stromal cell-derived factor 1 [sdf1, or CXC ligand 12 (CXCL12)] acts downstream from VEGF to mediate recruitment of BM sprocs, what the sdf1 receptor type [CXC receptor (CXCR)-4 or CXCR7] is on sprocs, and whether sdf1 signaling is required for normal liver regeneration. Studies were performed in the rat partial hepatectomy model. Tracking studies of BM sprocs were performed in wild-type Lewis rats that had undergone BM transplantation from transgenic enhanced green fluorescent protein-positive Lewis rats. Knockdown studies were performed using antisense oligonucleotides (ASOs). Expression of sdf1 doubles in liver and liver sinusoidal endothelial cells (LSECs) after partial hepatectomy. Upregulation of sdf1 expression increases proliferation of sprocs in the BM, mobilization of CXCR7+ BM sprocs to the circulation, and engraftment of CXCR7+ BM sprocs in the liver and promotes liver regeneration. Knockdown of hepatic VEGF with ASOs decreases hepatic sdf1 expression and plasma sdf1 levels. When the effect of VEGF knockdown on sdf1 is offset by infusion of sdf1, VEGF knockdown-induced impairment of BM sproc recruitment after partial hepatectomy is completely attenuated and liver regeneration is normalized. These data demonstrate that the VEGF-sdf1 pathway regulates recruitment of CXCR7+ BM sprocs to the hepatic sinusoid after partial hepatectomy and is required for normal liver regeneration.

Download Full-text

Platelet Transforming Growth Factor-β1 Induces Liver Sinusoidal Endothelial Cells to Secrete Interleukin-6

Cells ◽

10.3390/cells9051311 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1311

Author(s):

Alexandre Balaphas ◽

Jeremy Meyer ◽

Remo Perozzo ◽

Magali Zeisser-Labouebe ◽

Sarah Berndt ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Liver Regeneration ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Activated Platelets ◽

Platelet Releasate ◽

Tgf Β1

The roles and interactions of platelets and liver sinusoidal endothelial cells in liver regeneration are unclear, and the trigger that initiates hepatocyte proliferation is unknown. We aimed to identify the key factors released by activated platelets that induce liver sinusoidal endothelial cells to produce interleukin-6 (IL-6), a cytokine implicated in the early phase of liver regeneration. We characterized the releasate of activated platelets inducing the in vitro production of IL-6 by mouse liver sinusoidal endothelial cells and observed that the stimulating factor was a thermolabile protein. Following gel filtration, a single fraction of activated platelet releasate induced a maximal IL-6 secretion by liver sinusoidal endothelial cells (90.2 ± 13.9 versus control with buffer, 9.0 ± 0.8 pg/mL, p < 0.05). Mass spectroscopy analysis of this fraction, followed by in silico processing, resulted in a reduced list of 18 candidates. Several proteins from the list were tested, and only recombinant transforming growth factor β1 (TGF-β1) resulted in an increased IL-6 production up to 242.7 ± 30.5 pg/mL, which was comparable to non-fractionated platelet releasate effect. Using neutralizing anti-TGF-β1 antibody or a TGF-β1 receptor inhibitor, IL-6 production by liver sinusoidal endothelial cells was dramatically reduced. These results support a role of platelet TGF-β1 β1 in the priming phase of liver regeneration.

Download Full-text