title: Differential expression of syndecan-1 mediates cationic nanoparticle toxicity in undifferentiated versus differentiated normal human bronchial epithelial cells.
abstract: Most in vitro toxicity studies on engineered nanomaterials (ENMs) use transformed rather than primary cells for logistical reasons. However, primary cells may provide a more appropriate connection to in vivo toxicity because these cells maintain their phenotypic fidelity and are also capable of differentiating into lineages that may be differently affected by potentially hazardous ENMs. Few studies to date have focused on the role of cellular differentiation in determining ENM toxicity. We compared the response of undifferentiated and differentiated primary human bronchial epithelial (NHBE) cells to cationic mesoporous silica nanoparticles (MSNPs) that are coated with polyethyleneimine (PEI) since this polymer is known to exert differential cytotoxicity depending on its molecular weight and cationic density. The attachment of cationic PEI polymers to the MSNP surface was used to assess these materials' toxicological potential in undifferentiated and differentiated human bronchial epithelial cells, using a multiparametric assay that screens for an integrated set of sublethal and lethal response outcomes. MSNPs coated with high molecular weight (10 and 25 kD) polymers were more toxic in differentiated cells than particles coated with shorter length polymers. The increased susceptibility of the differentiated cells is in agreement with more abundant expression of a proteoglycan, syndecan-1, which contains copious heparin sulfate side chains. Pretreatment with heparinase to remove the negatively charged sulfates decreased MSNP-PEI binding to the cell surface and lowered the cytotoxic potential of the cationic particles. These data demonstrate the importance of studying cellular differentiation as an important variable in the response of primary cells to toxic ENM properties.
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of NanoMedicine, Department of Medicine, California, Los Angeles, California.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: Division of NanoMedicine, Department of Medicine, California, Los Angeles, California.
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.affiliation: Department of Chemistry & Biochemistry, California, Los Angeles, California.
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.|Division of NanoMedicine, Department of Medicine, California, Los Angeles, California.
authors.forename: Saji
authors.initials: S
authors.lastname: George
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Chemical & Biomolecular Engineering, California, Los Angeles, California.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.affiliation: Division of NanoMedicine, Department of Medicine, California, Los Angeles, California.
authors.forename: Meiying
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, California, Los Angeles, California.
authors.forename: Bryan
authors.initials: B
authors.lastname: France
authors.affiliation: Department of Chemical & Biomolecular Engineering, California, Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Rallo
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.|Molecular Shared Screening Resources, California, Los Angeles, California.
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.affiliation: Department of Chemical & Biomolecular Engineering, California, Los Angeles, California.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Cohen
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.|Department of Microbiology, Immunology & Molecular Genetics, California, Los Angeles, California.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bradley
authors.affiliation: Department of Chemistry & Biochemistry, California, Los Angeles, California.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.affiliation: California NanoSystems Institute at University of California, Los Angeles, California.|Division of NanoMedicine, Department of Medicine, California, Los Angeles, California.
authors.forename: Andre E
authors.initials: AE
authors.lastname: Nel
mesh_terms: D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002412:Cations; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D053668:Syndecan-1 / Q000378:metabolism*
chemical_list: D002412:Cations; D053668:Syndecan-1