title: A three-dimensionalex vivotri-culture model mimics cell-cell interactions between acute myeloid leukemia and the vascular niche.
abstract: Ex vivostudies of human disease, such as acute myeloid leukemia, are generally limited to the analysis of two-dimensional cultures which often misinterpret the effectiveness of chemotherapeutics and other treatments. Here we show that matrix metalloproteinase-sensitive hydrogels prepared from poly(ethylene glycol) and heparin functionalized with adhesion ligands and pro-angiogenic factors can be instrumental to produce robust three-dimensional culture models, allowing for the analysis of acute myeloid leukemia development and response to treatment. We evaluated the growth of four leukemia cell lines, KG1a, MOLM13, MV4-11 and OCI-AML3, as well as samples from patients with acute myeloid leukemia. Furthermore, endothelial cells and mesenchymal stromal cells were co-seeded to mimic the vascular niche for acute myeloid leukemia cells. Greater drug resistance to daunorubicin and cytarabine was demonstrated in three-dimensional cultures and in vascular co-cultures when compared with two-dimensional suspension cultures, opening the way for drug combination studies. Application of the C-X-C chemokine receptor type 4 (CXCR4) inhibitor, AMD3100, induced mobilization of the acute myeloid leukemia cells from the vascular networks. These findings indicate that the three-dimensional tri-culture model provides a specialized platform for the investigation of cell-cell interactions, addressing a key challenge of current testing models. Thisex vivosystem allows for personalized analysis of the responses of patients' cells, providing new insights into the development of acute myeloid leukemia and therapies for this disease.
authors.affiliation: Max Bergmann Center of Biomaterials, Leibniz Institute of Polymer Research Dresden, Germany Laura.bray@qut.edu.au.|Science and Engineering Faculty, Queensland University of Technology, Brisbane, Australia.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bray
authors.affiliation: Max Bergmann Center of Biomaterials, Leibniz Institute of Polymer Research Dresden, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Binner
authors.affiliation: Max Bergmann Center of Biomaterials, Leibniz Institute of Polymer Research Dresden, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Körner
authors.affiliation: Universitätsklinikum Carl-Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Saxony, Germany.|German Cancer Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), partner site Dresden, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: von Bonin
authors.affiliation: Universitätsklinikum Carl-Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Saxony, Germany.|German Cancer Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), partner site Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.affiliation: Max Bergmann Center of Biomaterials, Leibniz Institute of Polymer Research Dresden, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Werner
mesh_terms: D001596:Benzylamines; D015415:Biomarkers; D002450:Cell Communication; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000080027:Cyclams; D003561:Cytarabine / Q000494:pharmacology; D003630:Daunorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D009389:Neovascularization, Pathologic; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D001596:Benzylamines; D015415:Biomarkers; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D003561:Cytarabine; C088327:plerixafor; D003630:Daunorubicin