Hepatic Vascular Endothelial Growth Factor Regulates Recruitment of Rat Liver Sinusoidal Endothelial Cell Progenitor Cells

Abstract

Background & Aims After liver injury, bone marrow-derived liver sinusoidal endothelial cell progenitor cells (BM SPCs) repopulate the sinusoid as liver sinusoidal endothelial cells (LSECs). After partial hepatectomy, BM SPCs provide hepatocyte growth factor, promote hepatocyte proliferation, and are necessary for normal liver regeneration. We examined how hepatic vascular endothelial growth factor (VEGF) regulates recruitment of BM SPC and their effects on liver injury. Methods Rats were given injections of dimethylnitrosamine to induce liver injury, which was assessed by histology and transaminase assays. Recruitment of SPCs was analyzed by examining BM SPC proliferation, mobilization to the circulation, engraftment in liver, and development of fenestration (differentiation). Results Dimethylnitrosamine caused extensive denudation of LSEC at 24 hours, followed by centrilobular hemorrhagic necrosis at 48 hours. Proliferation of BM SPCs, number of SPCs in the bone marrow, and mobilization of BM SPCs to the circulation increased 2- to 4-fold by 24 hours after injection of dimethylnitrosamine; within 5 days, 40% of all LSEC came from engrafted BM SPC. Allogeneic resident SPCs, infused 24 hours after injection of dimethylnitrosamine, repopulated the sinusoid as LSEC and reduced liver injury. Expression of hepatic VEGF mRNA and protein increased 5-fold by 24 hours after dimethylnitrosamine injection. Knockdown of hepatic VEGF with antisense oligonucleotides completely prevented dimethylnitrosamine-induced proliferation of BM SPCs and their mobilization to the circulation, reduced their engraftment by 46%, completely prevented formation of fenestration after engraftment as LSEC, and exacerbated dimethylnitrosamine injury. Conclusions BM SPC recruitment is a repair response to dimethylnitrosamine liver injury in rats. Hepatic VEGF regulates recruitment of BM SPCs to liver and reduces this form of liver injury.

Sinusoidal communication in liver fibrosis and regeneration

“…These observations correlate with more recent work in which loss of LSEC viability occurs after 24h of liver injury, but before hepatocyte necrosis, suggesting that a VEGF-regulated engraftment of BM SPC, an alternative source of HGF, may latterly stimulate hepatocyte proliferation and liver regeneration [91]. Certainly, VEGF knockdown significantly decreases partial hepatectomy-induced BM SPC proliferation and engraftment to the liver [87]. These studies suggest that loss of LSEC functionality seems to be the input signalling in the bone marrow-liver crosstalk, which will promote the release of BM SPC, regeneration of the liver, and at a very final step reconstitution of LSEC structures will occur.…”

“…LSEC and HSC divide approximately 96h after partial hepatectomy, primarily due to hepatocyte-derived VEGF/angiopoietin stimulation, and proteins relying on phosphoinositide 3-kinase for their mitogenic effect, respectively [83–85]. There is an evident cooperation among non-parenchymal and parenchymal cells during regeneration [86], however, the idea that bone marrow-derived endothelial sinusoidal progenitor cells (BM SPC), rich in hepatocyte growth factor (HGF), are also recruited to the site of the injury is now emerging [87, 88]. Recently, Katagiri and colleagues observed that a small representation (1–2%) of bone marrow mesenchymal stem cells, named Muse, differentiate into liver-lineage cells and repair tissue.…”

Vascular pathobiology in chronic liver disease and cirrhosis – Current status and future directions

“…Further, in one study, reestablishment of LSEC fenestrae via restoration of VEGF function fully reversed portal hypertension and its secondary manifestations [8]. Finally, VEGF facilitates the recruitment of bone marrow-derived LSEC progenitor cells during liver regeneration [106]. Thus, the role of VEGF in liver injury, fibrosis, and portal hypertension, as well as its role in the recovery from these processes will require further exploration.…”

LYVE1 and PROX1 in the reconstruction of hepatic sinusoids after partial hepatectomy in mice

“…In addition, VEGF regulates the recruitment of rat liver progenitor sinusoidal endothelial cells to the liver, which is a crucial step for regeneration [29]. VEGF is a large family of 5 members in mammals, namely VEGFA, VEGFB, VEGFC, VEGFD, and placental growth factor.…”