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Open AccessArticle

Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis

1
Groningen Research Institute of Pharmacy, Department of Pharmacokinetics, Toxicology and Targeting, University of Groningen, 9713 AV Groningen, The Netherlands
2
Groningen Research Institute of Pharmacy, Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
3
UCL Institute for Liver and Digestive Health, University College London Division of Medicine, London NW3 2PF , UK
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(3), 278; https://doi.org/10.3390/pharmaceutics12030278 (registering DOI)
Received: 17 February 2020 / Revised: 12 March 2020 / Accepted: 17 March 2020 / Published: 20 March 2020
(This article belongs to the Special Issue Antifibrotic Drugs)
The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, proliferation, contraction, chemotaxis and inflammatory signaling. When determining the in vitro and in vivo effectivity of novel antifibrotic therapies, the readout is currently mainly based on gene and protein levels of α-smooth muscle actin (α-SMA) and the fibrillar collagens (type I and III). We advocate for a more comprehensive approach in addition to these markers when screening potential antifibrotic drugs that interfere with HSCs. Therefore, we aimed to develop a gene panel for human in vitro and ex vivo drug screening models, addressing each of the HSC-activities with at least one gene, comprising, in total, 16 genes. We determined the gene expression in various human stellate cells, ranging from primary cells to cell lines with an HSC-origin, and human liver slices and stimulated them with two key profibrotic factors, i.e., transforming growth factor β (TGFβ) or platelet-derived growth factor BB (PDGF-BB). We demonstrated that freshly isolated HSCs showed the strongest and highest variety of responses to these profibrotic stimuli, in particular following PDGF-BB stimulation, while cell lines were limited in their responses. Moreover, we verified these gene expression profiles in human precision-cut liver slices and showed similarities with the TGFβ- and PDGF-BB-related fibrotic responses, as observed in the primary HSCs. With this study, we encourage researchers to get off the beaten track when testing antifibrotic compounds by including more HSC-related markers in their future work. This way, potential compounds will be screened more extensively, which might increase the likelihood of developing effective antifibrotic drugs. View Full-Text
Keywords: drug development; primary hepatic stellate cells; precision-cut liver slices; myofibroblast; reversion; fibrosis gene panel; transforming growth factor β; platelet-derived growth factor BB drug development; primary hepatic stellate cells; precision-cut liver slices; myofibroblast; reversion; fibrosis gene panel; transforming growth factor β; platelet-derived growth factor BB
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van Dijk, F.; Hazelhoff, C.M.; Post, E.; Prins, G.G.H.; Rombouts, K.; Poelstra, K.; Olinga, P.; Beljaars, L. Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis. Pharmaceutics 2020, 12, 278.

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