The liver sinusoidal endothelial cell - the scrappy underdogs of hepatology

There are two pools of stem cells and liver sinusoidal endothelial cell progenitor cells (sprocs), one in the liver and the other in the bone marrow (BM). The BM sprocs play no role in turnover in adult rats, but repair LSECs... [ view full abstract ]

There are two pools of stem cells and liver sinusoidal endothelial cell progenitor cells (sprocs), one in the liver and the other in the bone marrow (BM). The BM sprocs play no role in turnover in adult rats, but repair LSECs in acute and chronic liver injury. We have demonstrated in several models of acute liver injury that VEGF increases in the liver, leading to an increase in sdf1 (CXCL12). This leads to increased proliferation of sprocs in the BM, an increased number of BM sprocs, mobilization of CXCR7+ BM sprocs to the circulation, engraftment of BM sprocs in the liver, and differentiation to LSECs. Irradiation of 40% of the BM suppresses liver regeneration by 40%, whereas timely infusion of either BM or BM sprocs restores normal liver regeneration. In fibrosis, BM sprocs are also recruited to the liver, but the BM-derived LSECs fail to fully mature as demonstrated by lack of fenestration organized in sieve plates, resulting in the process known as capillarization; in contrast, resident LSECs are normally fenestrated in cirrhotic liver. Fully mature LSECs maintain hepatic stellate cell quiescence by release of HB-EGF, but BM-derived LSECs in fibrosis are unable to release HB-EGF and the immature BM-derived LSECs are therefore permissive for hepatic stellate cell activation.