Thanapirom, K;
Caon, E;
Papatheodoridi, M;
Frenguelli, L;
Al-akkad, W;
Zhenzhen, Z;
Vilia, MG;
... Rombouts, K; + view all
(2021)
Optimization and validation of a novel three-dimensional co-culture system in decellularized human liver scaffold for the study of liver fibrosis and cancer.
Cancers
, 13
(19)
, Article 4936. 10.3390/cancers13194936.
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Abstract
The introduction of new preclinical models for in vitro drug discovery and testing based on 3D tissue-specific extracellular matrix (ECM) is very much awaited. This study was aimed at developing and validating a co-culture model using decellularized human liver 3D ECM scaffolds as a platform for anti-fibrotic and anti-cancer drug testing. Decellularized 3D scaffolds obtained from healthy and cirrhotic human livers were bioengineered with LX2 and HEPG2 as single and co-cultures for up to 13 days and validated as a new drug-testing platform. Pro-fibrogenic markers and cancer phenotypic gene/protein expression and secretion were differently affected when single and co-cultures were exposed to TGF-β1 with specific ECM-dependent effects. The anti-fibrotic efficacy of Sorafenib significantly reduced TGF-β1-induced pro-fibrogenic effects, which coincided with a downregulation of STAT3 phosphorylation. The anti-cancer efficacy of Regorafenib was significantly reduced in 3D bioengineered cells when compared to 2D cultures and dose-dependently associated with cell apoptosis by cleaved PARP-1 activation and P-STAT3 inhibition. Regorafenib re-versed TGF-β1-induced P-STAT3 and SHP-1 through induction of epithelial mesenchymal marker E-cadherin and downregulation of vimentin protein expression in both co-cultures engrafting healthy and cirrhotic 3D scaffolds. In their complex, the results of the study suggest that this newly proposed 3D co-culture platform is able to reproduce the natural physio-pathological microenvi-ronment and could be employed for anti-fibrotic and anti-HCC drug screening.
| Type: | Article |
|---|---|
| Title: | Optimization and validation of a novel three-dimensional co-culture system in decellularized human liver scaffold for the study of liver fibrosis and cancer |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/cancers13194936 |
| Publisher version: | https://doi.org/10.3390/cancers13194936 |
| Language: | English |
| Additional information: | © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). |
| Keywords: | decellularized liver scaffolds; drug screening; liver fibrosis; liver cancer; sorafenib; regorafenib; STAT3; SHP-1; TGFβ1; EMT; E-cadherin; 3D in vitro model |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10136333 |
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