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

Sheng Cao, Usman Yaqoob, Amitava Das, Uday Shergill, Kumaravelu Jagavelu, Robert C Huebert, Chittaranjan Routray, Soha Abdelmoneim, Meher Vasdev, Edward B Leof, Michael Charlton, Ryan J. Watts, Debabrata Mukhopadhyay, Vijay Shah

Research output: Contribution to journalArticle

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Abstract

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 β (PDGFRβ) 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-β-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 PDGFRβ-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.

Original languageEnglish (US)
Pages (from-to)2379-2394
Number of pages16
JournalJournal of Clinical Investigation
Volume120
Issue number7
DOIs
StatePublished - Jul 1 2010

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Neuropilin-1
Hepatic Stellate Cells
Rodentia
Fibrosis
Liver Cirrhosis
Liver
Platelet-Derived Growth Factor Receptors
Myofibroblasts
Blood Vessels
Wounds and Injuries
Chemotaxis
Fatty Liver
Hepatitis C
Immunoprecipitation
Vascular Endothelial Growth Factor A
Small Interfering RNA
Cell Movement
Intercellular Signaling Peptides and Proteins
Collagen
Endothelial Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells. / Cao, Sheng; Yaqoob, Usman; Das, Amitava; Shergill, Uday; Jagavelu, Kumaravelu; Huebert, Robert C; Routray, Chittaranjan; Abdelmoneim, Soha; Vasdev, Meher; Leof, Edward B; Charlton, Michael; Watts, Ryan J.; Mukhopadhyay, Debabrata; Shah, Vijay.

In: Journal of Clinical Investigation, Vol. 120, No. 7, 01.07.2010, p. 2379-2394.

Research output: Contribution to journalArticle

Cao, S, Yaqoob, U, Das, A, Shergill, U, Jagavelu, K, Huebert, RC, Routray, C, Abdelmoneim, S, Vasdev, M, Leof, EB, Charlton, M, Watts, RJ, Mukhopadhyay, D & Shah, V 2010, 'Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells', Journal of Clinical Investigation, vol. 120, no. 7, pp. 2379-2394. https://doi.org/10.1172/JCI41203
Cao, Sheng ; Yaqoob, Usman ; Das, Amitava ; Shergill, Uday ; Jagavelu, Kumaravelu ; Huebert, Robert C ; Routray, Chittaranjan ; Abdelmoneim, Soha ; Vasdev, Meher ; Leof, Edward B ; Charlton, Michael ; Watts, Ryan J. ; Mukhopadhyay, Debabrata ; Shah, Vijay. / Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 7. pp. 2379-2394.
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AU - Shergill, Uday

AU - Jagavelu, Kumaravelu

AU - Huebert, Robert C

AU - Routray, Chittaranjan

AU - Abdelmoneim, Soha

AU - Vasdev, Meher

AU - Leof, Edward B

AU - Charlton, Michael

AU - Watts, Ryan J.

AU - Mukhopadhyay, Debabrata

AU - Shah, Vijay

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AB - 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 β (PDGFRβ) 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-β-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 PDGFRβ-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.

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