VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration

Laurie D DeLeve, Xiangdong Wang, Lei Wang

In liver injury, recruitment of bone marrow progenitors of liver sinusoidal endothelial cells (now named sprocs) is necessary for normal liver regeneration. Hepatic VEGF is a central regulator of the recruitment process. Here we examine whether stromal cell derived factor-1 (sdf-1 or CXCL-12) acts downstream from VEGF to mediate recruitment of bone marrow sprocs, what the sdf-1 receptor type (CXCR4 or CXCR7) is on sprocs, and whether sdf-1 signaling is required for normal liver regeneration. Studies were performed in the rat partial hepatectomy model. Tracking studies of bone marrow sprocs were performed in wild type Lewis rats that had undergone bone marrow transplantation from transgenic EGFP+ Lewis rats. Knockdown studies were performed using anti-sense oligonucleotides. Expression of sdf-1 doubles in liver and in LSECs after partial hepatectomy. The upregulation of sdf-1 expression increases proliferation of sprocs in the bone marrow, mobilization of CXCR7+ bone marrow sprocs to the circulation, and engraftment of CXCR7+ bone marrow sprocs in the liver, and promotes liver regeneration. Knockdown of hepatic VEGF with anti-sense oligonucleotides decreases hepatic sdf-1 expression and plasma sdf-1 levels. When the effect of VEGF knockdown on sdf-1 is offset by infusion of sdf-1, 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-sdf-1 pathway regulates recruitment of CXCR7+ bone marrow sprocs to the hepatic sinusoid after partial hepatectomy and is required for normal liver regeneration.