Cited by 111Liver physiology and pathologyExtracellular vesicles in diseaseLiver Disease Diagnosis and Treatment

Hepatic stellate cell–derived platelet‐derived growth factor receptor‐alpha‐enriched extracellular vesicles promote liver fibrosis in mice through SHP2

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Kostallari, Enis, Hirsova, Petra, Prasnicka, Alena, Verma, Vikas K., Yaqoob, Usman, Wongjarupong, Nicha, Roberts, Lewis R., Shah, Vijay H.·2018·Hepatology

Abstract

Liver fibrosis is characterized by the activation and migration of hepatic stellate cells (HSCs), followed by matrix deposition. Recently, several studies have shown the importance of extracellular vesicles (EVs) derived from liver cells, such as hepatocytes and endothelial cells, in liver pathobiology. While most of the studies describe how liver cells modulate HSC behavior, an important gap exists in the understanding of HSC-derived signals and more specifically HSC-derived EVs in liver fibrosis. Here, we investigated the molecules released through HSC-derived EVs, the mechanism of their release, and the role of these EVs in fibrosis. Mass spectrometric analysis showed that platelet-derived growth factor (PDGF) receptor-alpha (PDGFRα) was enriched in EVs derived from PDGF-BB-treated HSCs. Moreover, patients with liver fibrosis had increased PDGFRα levels in serum EVs compared to healthy individuals. Mechanistically, in vitro tyrosine720-to-phenylalanine mutation on the PDGFRα sequence abolished enrichment of PDGFRα in EVs and redirected the receptor toward degradation. Congruently, the inhibition of Src homology 2 domain tyrosine phosphatase 2, the regulatory binding partner of phosphorylated tyrosine720, also inhibited PDGFRα enrichment in EVs. EVs derived from PDGFRα-overexpressing cells promoted in vitro HSC migration and in vivo liver fibrosis. Finally, administration of Src homology 2 domain tyrosine phosphatase 2inhibitor, SHP099, to carbon tetrachloride-administered mice inhibited PDGFRα enrichment in serum EVs and reduced liver fibrosis. CONCLUSION: PDGFRα is enriched in EVs derived from PDGF-BB-treated HSCs in an Src homology 2 domain tyrosine phosphatase 2-dependent manner and these PDGFRα-enriched EVs participate in development of liver fibrosis. (Hepatology 2018;68:333-348).

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Authors
Kostallari, E., Hirsova, P., Prasnicka, A., Verma, V. K., Yaqoob, U., Wongjarupong, N., Roberts, L. R., & Shah, V. H.
Affiliations
Mayo Clinic (US)
Corresponding author
Shah, Vijay H.
Venue
Hepatology
Published
2018-07
Volume
68
Issue
1
Pages
333-348
ISSN
0270-9139 (ISSN-L)
OpenAlex
W2793191892
Cited by
111
References
49
Citations by year
2026: 5 · 2025: 11 · 2024: 17 · 2023: 11 · 2022: 17 · 2021: 16 · 2020: 18 · 2019: 12 · 2018: 3
FWCI
7.78
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mayo Clinic (P30 DK084567)
  • American Liver Foundation
  • American Association for the Study of Liver Diseases
  • Gilead Sciences
  • Ariad Pharmaceuticals
  • National Institutes of Health
  • Center for Cell Signaling in Gastroenterology, Mayo Clinic (P30 DK084567)
  • National Institute on Alcohol Abuse and Alcoholism (R01AA021171, R37AA021171)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK059615, P30DK084567)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
liver fibrosis, hepatic stellate cells, extracellular vesicles, PDGFRA, PDGF-BB, SHP2, SHP099, carbon tetrachloride, serum extracellular vesicles
MeSH terms
Extracellular Vesicles, Adult, Animals, Cell Movement, Female, Humans, Liver Cirrhosis, Male, Mice, Inbred C57BL, Middle Aged, Receptor, Platelet-Derived Growth Factor alpha, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Hepatic Stellate Cells, Young Adult

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