Bioinstructive microparticles for self-assembly of mesenchymal stem Cell-3D tumor spheroids
authors Ferreira, LP; Gaspar, VM; Mano, JF
nationality International
journal BIOMATERIALS
author keywords 3D In vitro tumor models; Co-culture; Bioinstructive microparticles; Drug screening; Lung cancer; Mesenchymal stem cells
keywords LUNG-CANCER CELLS; DOUBLE-EDGED-SWORD; HYALURONIC-ACID; MULTIDRUG-RESISTANCE; DRUG DISCOVERY; KEY PLAYERS; 3D; CULTURE; MICROENVIRONMENT; FIBROBLASTS
abstract 3D multicellular tumor spheroids (3D-MCTS) that closely mimic in vitro the complex lung tumor micro environment (TME) are highly desirable for screening innovative anti-cancer therapeutics. Despite significant improvements in mimicking lung TME, few models have combined tumor-infiltrating mesenchymal stem cells from bone marrow (hBM-MSCs) with heterotypic 3D tumor spheroid models containing ECM mimetic components. Herein, we engineered hybrid 3D-MCTS that combine, for the first time, A549:fibroblasts:hBM-MSCs in heterotypic tri-culture, with bioinstructive hyaluronan microparticles that act as tumor-ECM mimetics and as cell-anchoring hotspots. The obtained results indicated that 3D microspheres provided proper support for cells to self-assemble into compact 3D microtissues and promoted an increase in CD44 expression, emulating the presence of native-ECM hyaluronan. 3D-MCTS size and sphere-like morphology was reproducible and tri-culture models presented the characteristic solid tumors necrotic core. Mesenchymal stem cells tracking demonstrated that hBM-MSCs migrate to different regions in 3D microtumors mass exhibiting dynamic interactions with cancer cells and stromal fibroblasts, alike in human tumors. Importantly, doxorubicin administration revealed hBM-MSCs effect on cytotoxic responses in 3D tri-culture models and in dual cultures of hBM-MSCs:A549 at 10:1 ratio. Such findings evidence the relevance of including hBM-MSCs in combination with cancer-stromal fibroblasts in 3D in vitro tumor models and the importance to test different cell-to-cell ratios to mimic tumor heterogeneity. In addition, bioinstructive hyaluronan-microparticles were also effective as cell-agglomerating scaffolds and showed potential to be used as an enabling technology for including different ECM components in 3D in vitro models in the future.
publisher ELSEVIER SCI LTD
issn 0142-9612
year published 2018
volume 185
beginning page 155
ending page 173
digital object identifier (doi) 10.1016/j.biomaterials.2018.09.007
web of science category Engineering, Biomedical; Materials Science, Biomaterials
subject category Engineering; Materials Science
unique article identifier WOS:000448494500014
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journal analysis (jcr 2017):
journal impact factor 8.806
5 year journal impact factor 9.315
category normalized journal impact factor percentile 98.922
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