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Cirrhotic Human Liver Extracellular Matrix 3D Scaffolds Promote Smad-Dependent TGF-β1 Epithelial Mesenchymal Transition

1
Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College London (UCL), London NW3 2PF, UK
2
Engitix Ltd., London NW3 2PF, UK
3
Proteomics and Molecular Cell Dynamics, Centre for Nephrology, School of Life and Medical Sciences, University College London, London NW3 2PF, UK
4
Stem Cells and Regenerative Medicine Section, Developmental Biology and Cancer Programme, UCL Institute for Child Health, Great Ormond Street Hospital, University College London, London WC1N 3JH, UK
5
Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 205-207, 2730 Herlev, Denmark
6
Department of Bioengineering, Cellular and Molecular Biomechanics, Imperial College, London SW7 2AZ, UK
7
Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2PF, UK
8
Specialist Neonatal and Paediatric Surgery at Great Ormond Street Hospital, London WC1N 3JH, UK
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(1), 83; https://doi.org/10.3390/cells9010083
Received: 29 November 2019 / Revised: 23 December 2019 / Accepted: 24 December 2019 / Published: 28 December 2019
(This article belongs to the Special Issue Recent Advances in Liver Repair Strategies)
An altered liver microenvironment characterized by a dysregulated extracellular matrix (ECM) supports the development and progression of hepatocellular carcinoma (HCC). The development of experimental platforms able to reproduce these physio-pathological conditions is essential in order to identify and validate new therapeutic targets for HCC. The aim of this work was to validate a new in vitro model based on engineering three-dimensional (3D) healthy and cirrhotic human liver scaffolds with HCC cells recreating the micro-environmental features favoring HCC. Healthy and cirrhotic human livers ECM scaffolds were developed using a high shear stress oscillation-decellularization procedure. The scaffolds bio-physical/bio-chemical properties were analyzed by qualitative and quantitative approaches. Cirrhotic 3D scaffolds were characterized by biomechanical properties and microarchitecture typical of the native cirrhotic tissue. Proteomic analysis was employed on decellularized 3D scaffolds and showed specific enriched proteins in cirrhotic ECM in comparison to healthy ECM proteins. Cell repopulation of cirrhotic scaffolds highlighted a unique up-regulation in genes related to epithelial to mesenchymal transition (EMT) and TGFβ signaling. This was also supported by the presence and release of higher concentration of endogenous TGFβ1 in cirrhotic scaffolds in comparison to healthy scaffolds. Fibronectin secretion was significantly upregulated in cells grown in cirrhotic scaffolds in comparison to cells engrafted in healthy scaffolds. TGFβ1 induced the phosphorylation of canonical proteins Smad2/3, which was ECM scaffold-dependent. Important, TGFβ1-induced phosphorylation of Smad2/3 was significantly reduced and ECM scaffold-independent when pre/simultaneously treated with the TGFβ-R1 kinase inhibitor Galunisertib. In conclusion, the inherent features of cirrhotic human liver ECM micro-environment were dissected and characterized for the first time as key pro-carcinogenic components in HCC development. View Full-Text
Keywords: hepatocellular carcinoma (HCC); tumor microenvironment (TME); 3-dimensional (3D) platform; 3D ECM scaffolds; decellularized human liver; decellularized extracellular matrix (dECM); proteomics; hepatocellular carcinoma cells; Transforming growth factor beta1 (TGF-β1); tissue engineering hepatocellular carcinoma (HCC); tumor microenvironment (TME); 3-dimensional (3D) platform; 3D ECM scaffolds; decellularized human liver; decellularized extracellular matrix (dECM); proteomics; hepatocellular carcinoma cells; Transforming growth factor beta1 (TGF-β1); tissue engineering
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Mazza, G.; Telese, A.; Al-Akkad, W.; Frenguelli, L.; Levi, A.; Marrali, M.; Longato, L.; Thanapirom, K.; Vilia, M.G.; Lombardi, B.; Crowley, C.; Crawford, M.; Karsdal, M.A.; Leeming, D.J.; Marrone, G.; Bottcher, K.; Robinson, B.; Del Rio Hernandez, A.; Tamburrino, D.; Spoletini, G.; Malago, M.; Hall, A.R.; Godovac-Zimmermann, J.; Luong, T.V.; De Coppi, P.; Pinzani, M.; Rombouts, K. Cirrhotic Human Liver Extracellular Matrix 3D Scaffolds Promote Smad-Dependent TGF-β1 Epithelial Mesenchymal Transition. Cells 2020, 9, 83.

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