Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells.
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.
Cao
Sheng
S
Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA. sheng@mayo.edu
Yaqoob
Usman
U
Das
Amitava
A
Shergill
Uday
U
Jagavelu
Kumaravelu
K
Huebert
Robert C
RC
Routray
Chittaranjan
C
Abdelmoneim
Soha
S
Vasdev
Meher
M
Leof
Edward
E
Charlton
Michael
M
Watts
Ryan J
RJ
Mukhopadhyay
Debabrata
D
Shah
Vijay H
VH
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D055166:Hepatic Stellate Cells; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D039942:Neuropilin-1 / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D012377:Rodentia / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
D036341:Intercellular Signaling Peptides and Proteins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A; D039942:Neuropilin-1; D003094:Collagen; D020797:Receptor, Platelet-Derived Growth Factor beta