Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells.

Publication Type:

Journal Article


The Journal of clinical investigation, Volume 120, Issue 7, p.2379-94 (2010)


Animalsdigestive disease, digestive deseases Cell Movementdigestive disease, digestive deseases Cells, Cultureddigestive disease, digestive deseases Collagendigestive disease, digestive deseases Extracellular Matrixdigestive disease, digestive deseases Fibrosisdigestive disease, digestive deseases Hepatic Stellate Cellsdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Immunoprecipitationdigestive disease, digestive deseases Intercellular Signaling Peptides and Proteinsdigestive disease, digestive deseases Liverdigestive disease, digestive deseases Liver Cirrhosisdigestive disease, digestive deseases Micedigestive disease, digestive deseases Neuropilin-1digestive disease, digestive deseases Platelet-Derived Growth Factordigestive disease, digestive deseases Receptor, Platelet-Derived Growth Factor betadigestive disease, digestive deseases Rodentiadigestive disease, digestive deseases Signal Transductiondigestive disease, digestive deseases Transforming Growth Factor beta


PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, the mechanisms that regulate PDGF signaling remain incompletely defined. Here, we found that in two rat models of liver fibrosis, the axonal guidance molecule neuropilin-1 (NRP-1) was upregulated in activated HSCs, which exhibit the highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor beta (PDGFRbeta) in HSCs both in the injury models and in human and rat HSC cell lines. In human HSCs, siRNA-mediated knockdown of NRP-1 attenuated PDGF-induced chemotaxis, while NRP-1 overexpression increased cell motility and TGF-beta-dependent collagen production. Similarly, mouse HSCs genetically modified to lack NRP-1 displayed reduced motility in response to PDGF treatment. Immunoprecipitation and biochemical binding studies revealed that NRP-1 increased PDGF binding affinity for PDGFRbeta-expressing cells and promoted downstream signaling. An NRP-1 neutralizing Ab ameliorated recruitment of HSCs, blocked liver fibrosis in a rat model of liver injury, and also attenuated VEGF responses in cultured liver endothelial cells. In addition, NRP-1 overexpression was observed in human specimens of liver cirrhosis caused by both hepatitis C and steatohepatitis. These studies reveal a role for NRP-1 as a modulator of multiple growth factor targets that regulate liver fibrosis and the vascular changes that accompany it and may have broad implications for liver cirrhosis and myofibroblast biology in a variety of other organ systems and disease conditions.