title: Elucidation of adhesion-dependent spontaneous apoptosis in macrophages using phase separated PEG/polyurethane films.
abstract: Circulating monocytes undergo spontaneous apoptosis when there is no activation stimulus, which is critical to population control for proper host response to implants. As activation and apoptosis of monocytes/macrophages are regulated by cell-cell and cell-matrix interactions, their regulatory mechanism was investigated in this study using polyethylene glycol (PEG)-containing polyurethane films in which PEG-rich and polyester-rich domains were phase separated. Human blood monocyte-derived macrophages (HBMs) preferentially adhered to PEG domains (cell-matrix interaction) due to the low molecular weight (600 g mol⁻¹), resulting in increased HBM density (cell-cell interaction). As both cell-cell and cell-matrix interactions were promoted, HBM apoptosis increased, while their activation as measured by phagocytosis, intracellular reactive oxygen species (ROS) level and matrix metalloproteinase-9 production decreased compared to PEG-free films. When cell seeding density and cell-adhesive gelatin coating on silicone films were controlled, a cooperative role of cell-matrix (adhesion) and cell-cell (density) interactions in inducing HBM apoptosis was observed. Expression of the macrophage adhesion molecule CD11b caused apoptosis in this context, which was mediated by tissue necrosis factor-α signaling but down-regulated by the ROS inhibitor diphenylene iodonium and the anti-inflammatory peptide Ac-SDKP, suggesting a new concept for the design of biomaterials that allows for cell adhesion without excessive inflammatory activation.
authors.affiliation: Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Zachman
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Page
authors.forename: Gayathri
authors.initials: G
authors.lastname: Prabhakar
authors.forename: Scott A
authors.initials: SA
authors.lastname: Guelcher
authors.forename: Hak-Joon
authors.initials: HJ
authors.lastname: Sung
mesh_terms: D000327:Adsorption / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000473:pathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D011140:Polyurethanes / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D016207:Cytokines; D011140:Polyurethanes; D017382:Reactive Oxygen Species; D011092:Polyethylene Glycols; D003094:Collagen; D020780:Matrix Metalloproteinase 9