eprintid: 10136333
rev_number: 13
eprint_status: archive
userid: 608
dir: disk0/10/13/63/33
datestamp: 2021-10-13 10:58:10
lastmod: 2022-09-09 14:32:27
status_changed: 2021-10-13 10:58:10
type: article
metadata_visibility: show
creators_name: Thanapirom, K
creators_name: Caon, E
creators_name: Papatheodoridi, M
creators_name: Frenguelli, L
creators_name: Al-akkad, W
creators_name: Zhenzhen, Z
creators_name: Vilia, MG
creators_name: Pinzani, M
creators_name: Mazza, G
creators_name: Rombouts, K
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
ispublished: pub
subjects: RFH
divisions: UCL
divisions: B02
divisions: C10
divisions: D17
divisions: G91
keywords: decellularized liver scaffolds; drug screening; liver fibrosis; liver cancer; sorafenib; regorafenib; STAT3; SHP-1; TGFβ1; EMT; E-cadherin; 3D in vitro model
note: © 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/).
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.
date: 2021-09-30
date_type: published
official_url: https://doi.org/10.3390/cancers13194936
oa_status: green
full_text_type: pub
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1892816
doi: 10.3390/cancers13194936
lyricists_name: Pinzani, Massimo
lyricists_name: Rombouts, Krista
lyricists_id: MPINZ74
lyricists_id: KROMB89
actors_name: Barczynska, Patrycja
actors_id: PBARC91
actors_role: owner
full_text_status: public
publication: Cancers
volume: 13
number: 19
article_number: 4936
issn: 2072-6694
citation:        Thanapirom, K;    Caon, E;    Papatheodoridi, M;    Frenguelli, L;    Al-akkad, W;    Zhenzhen, Z;    Vilia, MG;             ... Rombouts, K; + view all <#>        Thanapirom, K;  Caon, E;  Papatheodoridi, M;  Frenguelli, L;  Al-akkad, W;  Zhenzhen, Z;  Vilia, MG;  Pinzani, M;  Mazza, G;  Rombouts, K;   - view fewer <#>    (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 <https://doi.org/10.3390/cancers13194936>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10136333/1/Pinzani_cancers-13-04936-v2.pdf