Dissecting stromal-epithelial interactions in a 3D in vitro cellularized intestinal model for permeability studies |
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| Institution: | 1. I3S – Instituto de Investigação e Inovação em Saúde and INEB – Instituto de Engenharia Biomédica, University of Porto, Rua do Campo Alegre, 823, 4150-180, Porto, Portugal;2. FEUP – Faculdade de Engenharia, University of Porto, Rua Dr. Roberto Frias, 4200-465, Porto, Portugal;3. ICBAS – Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Rua de Jorge Viterbo Ferreira, 4050-313, Porto, Portugal;4. CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Superior de Ciências da Saúde-Norte, Rua Central de Grandra, 1317, 4585-116, Gandra, Portugal;1. Rensselaer Nanotechnology Center, Rensselear Polytechnic Institute, Troy, NY 12180, United States;2. Department of Materials Science and Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States;3. Department of Chemical and Biological Engineering, Rensselaer Polytechnic Institute, Troy, NY 12180, United States;4. Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180, United States;5. Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY 12180, United States;1. Institute for Research in Biomedicine, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland;2. Novartis Institute for Biomedical Research, Fabrickstrasse 2, 4002 Basel, Switzerland;3. Graduate School for Cellular and Biomedical Sciences, University of Bern, Freiestrasse 1, 3012 Bern, Switzerland;4. Fondazione Filarete, Viale Ortles 22/4, 20139 Milan, Italy;5. Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza 35, 20122 Milan, Italy;6. Unit of Gastroenterology 2, Fondazione IRCCS Ca’ Granda, Ospedale Policlinico di Milano, Via Francesco Sforza 35, 20122 Milan, Italy;7. Department of Veterinary Medical Sciences, University of Camerino, Via Circonvallazione 93/95, 62024 Matelica, Italy;8. Maurice Müller Laboratories, Universitätsklinik für Viszerale Chirurgie und Medizin (UVCM), University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland;9. Institute of Microbiology, ETH Zurich, HCI F 413 Vladimir-Prelog-Weg 1-5/10, 8093 Zurich, Switzerland;10. Department of Medical Biotechnology and Translational Medicine, University of Milan, Via G.B. Viotti 3/5, 20133 Milan, Italy;1. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA;2. Department of Chemical Engineering, Northeastern University, Boston, MA, USA;3. Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, USA;1. Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan;2. Department of Pathopharmacology, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, 862-0973, Japan;1. Biomedical Sciences Research Centre “Alexander Fleming,” Vari, Greece;2. Muhimbili University of Health and Allied Sciences, School of Medicine, Dar es Salaam, Tanzania;3. Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany;4. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany;5. Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece;1. Laboratory of Immunology and Cellular and Molecular Biology, Faculty of Chemical Sciences, UASLP, San Luis Potosí, S.L.P., Mexicohttp://10.10.23.110:8080/TDXPSLIVELATEX/gateway/elsevierjournal/index.jsp#;2. Division of Molecular Biology, Instituto Potosino de Investigación Científica y Tecnológica, San Luis Potosí, S.L.P. Mexico;3. Unit of Medicine Investigation IMSS, Zacatecas, Zac, Mexico;4. Department of Immunology, Faculty of Medicine, UASLP, San Luis Potosí, S.L.P. Mexico |
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| Abstract: | Absorption evaluation plays an increasingly important role at the early stage of drug discovery due to its potential to scan the ADME (absorption, distribution, metabolism and excretion) properties of new drug candidates. Therefore, a new three-dimensional (3D) in vitro model replicating the intestinal functioning is herein proposed aiming to dissect the stromal-epithelial interactions and evaluate the permeation of a model drug, insulin. Inspired on the intestinal mucosal architecture, the present model comprises intestinal myofibroblasts (CCD18-Co cells) embedded in Matrigel, onto which epithelial enterocytes (Caco-2 cells) and mucus-producing cells (HT29-MTX cells) were seeded. CCD18-Co myofibroblasts showed to have a central role in the remodeling of the surrounding matrix confirmed by the production of fibronectin. Subsequently, this matrix revealed to be essential to the maintenance of the model architecture by supporting the overlying epithelial cells. In terms of functionality, this model allowed the efficient prediction of insulin permeability in which the presence of mucus, the less tight character between Caco-2 and HT29-MTX epithelial cells and the 3D assembly were critical factors. Concluding, this model constitutes a robust tool in the drug development field with potential to bridge the traditional 2D cell culture models and in vivo animal models. |
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| Keywords: | Intestinal mucosa Triple co-culture Extracellular matrix (ECM) Fibroblast Caco-2 cells HT29-MTX cells |
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