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Extrahepatic Platelet-Derived Growth Factor-β, Delivered by Platelets, Promotes Activation of Hepatic Stellate Cells and Biliary Fibrosis in Mice
Open accessAbstract
Background & aims Platelet-derived growth factor-β (PDGFB) is a mitogen for hepatic stellate cells (HSCs). We studied the cellular sources of PDGFB and the effects of a high-affinity monoclonal antibody against PDGFB (MOR8457) in mouse models of biliary fibrosis.Methods Cellular sources of PDGFB were identified using quantitative reverse-transcription polymerase chain reaction, biochemical, and immunohistologic methods. Mice with advanced biliary fibrosis, MDR2(Abcb4)-null mice, and C57Bl/6 (control) mice were placed on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diets and were given weekly intraperitoneal injections of MOR8457. Platelets were depleted from MDR2-null mice by injection of an antibody against CD41, or inhibited with diets containing low-dose aspirin. Liver tissues were collected and analyzed by quantitative reverse-transcription PCR and histologic and biochemical analyses.Results Levels of PDGFB protein, but not messenger RNA, were increased in fibrotic livers of MDR2-null mice, compared with control mice. Platelet clusters were detected in the hepatic endothelium, in close proximity to HSCs, and were identified as a source of PDGFB protein in MDR2-null mice. Levels of the PDGFB were increased in serum samples from patients with early stages of liver fibrosis of various etiologies (F1-2, n = 16; P < .05), compared with nonfibrotic liver tissue (F0, n = 12). Depletion of platelets from MDR2-null mice normalized hepatic levels of PDGFB within 48 hours, reducing levels of a marker of HSC activation (α-smooth muscle actin) and expression of genes that promote fibrosis. Diets supplemented with low-dose aspirin reduced circulating serum and hepatic levels of PDGFB and significantly reduced progression of fibrosis in MDR2-null mice over 1 year. MOR8457 produced a dose-dependent decrease in liver fibrosis in MDR2-null mice, reducing collagen deposition by 45% and expression of fibrosis-associated genes by 50%, compared with mice given a control antibody. In vitro, platelets activated freshly isolated HSCs (induction of α-smooth muscle actin and fibrosis-associated genes) via a PDGFB-dependent mechanism. MOR8457 also reduced liver fibrosis in mice placed on DDC-supplemented diets.Conclusions Platelets produce PDGFB to activate HSC and promote fibrosis in MDR2-null mice and mice on DDC-supplemented diets. Antiplatelet therapy or selective inhibition of PDGFB might reduce biliary fibrosis in patients with liver disease.
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“In NASH, platelets interact with liver-resident KCs to promote the recruitment of CD8 T cells and NKT cells, depending on interactions between platelet-expressed GPIba and von Willebrand factor, thereby promoting disease.98”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [98]
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Metadata
- Authors
- Yoshida, S., Ikenaga, N., Liu, S. B., Peng, Z.-W., Chung, J., Sverdlov, D. Y., Miyamoto, M., Kim, Y. O., Ogawa, S., Arch, R. H., Schuppan, D., & Popov, Y.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Pfizer (United States) (US)
- Corresponding author
- Popov, Yury
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 147
- Issue
- 6
- Pages
- 1378-1392
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2121815683
- Cited by
- 164
- References
- 36
- Citations by year
- 2026: 8 · 2025: 19 · 2024: 13 · 2023: 15 · 2022: 18 · 2021: 15 · 2020: 17 · 2019: 14 · 2018: 5 · 2017: 21 · 2016: 10 · 2015: 8 · 2014: 1
- FWCI
- 7.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Tokyo Women's Medical University
- Takeda Pharmaceuticals International
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- platelet-derived growth factor beta, hepatic stellate cell activation, biliary fibrosis, liver fibrosis, platelets, low-dose aspirin, platelet depletion, CD41, alpha-smooth muscle actin, collagen deposition, fibrosis biomarkers
- MeSH terms
- ATP-Binding Cassette Sub-Family B Member 4, Adult, Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal, Aspirin, Blood Platelets, Disease Models, Animal, Female, Humans, Liver Cirrhosis, Male, Mice, Inbred C57BL, Middle Aged, Platelet Aggregation Inhibitors, RNA, Messenger, Bile Ducts, Extrahepatic, Mice, Knockout, ATP Binding Cassette Transporter, Subfamily B, Proto-Oncogene Proteins c-sis, Hepatic Stellate Cells, Antibodies, Neutralizing
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