Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells.
OBJECTIVE
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 SPCs 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 LSECs at 24 hours, followed by centrilobular hemorrhagic necrosis at 48 hours. Proliferation of BM SPCs, the 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 LSECs came from engrafted BM SPCs. Allogeneic resident SPCs, infused 24 hours after injection of dimethylnitrosamine, repopulated the sinusoid as LSECs and reduced liver injury. Expression of hepatic VEGF messenger RNA 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 LSECs, 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.
Division of Gastrointestinal and Liver Disease and the University of Southern California Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Lin
L
Wang
Xiangdong
X
Wang
Lei
L
Wang
Jenny D
JD
Chiu
Gijs
G
van de Ven
William A
WA
Gaarde
Laurie D
LD
Deleve
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology* / Q000517:prevention & control; D004128:Dimethylnitrosamine / Q000009:adverse effects; D042783:Endothelial Cells / Q000473:pathology*; D006498:Hepatectomy; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000473:pathology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D042461:Vascular Endothelial Growth Factor A; D004128:Dimethylnitrosamine