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Elucidation of adhesion-dependent spontaneous apoptosis in macrophages using phase separated PEG/polyurethane films
Angela L Zachman1, Jonathan M Page, Gayathri Prabhakar
1Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA.
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.
Insights
Biomaterials can control immune cell behavior. This study shows that specific material properties promote monocyte apoptosis, reducing inflammation for better implant responses.
Area of Science:
- Biomaterials Science
- Immunology
- Cell Biology
Background:
- Circulating monocytes undergo apoptosis to regulate host immune responses, especially around implants.
- Monocyte/macrophage activation and apoptosis are influenced by cell-cell and cell-matrix interactions.
- Understanding these interactions is key to designing effective biomaterials.
Purpose of the Study:
- To investigate the regulatory mechanisms of monocyte/macrophage apoptosis and activation.
- To explore the role of cell-cell and cell-matrix interactions in biomaterial response.
- To inform the design of biomaterials that promote controlled immune cell behavior.
Main Methods:
- Utilized polyethylene glycol (PEG)-containing polyurethane films with phase-separated domains.
- Examined human blood monocyte-derived macrophages (HBMs) adhesion and density on PEG-rich domains.
- Assessed HBM apoptosis, phagocytosis, reactive oxygen species (ROS) levels, and matrix metalloproteinase-9 production.
- Controlled cell seeding density and gelatin coating on silicone films.
Main Results:
- HBMs preferentially adhered to low molecular weight PEG domains, increasing cell density.
- Promoted cell-cell and cell-matrix interactions led to increased HBM apoptosis.
- Biomaterial interactions decreased HBM activation markers (phagocytosis, ROS, MMP-9).
- CD11b expression induced apoptosis via TNF-α signaling, modulated by ROS and anti-inflammatory peptide Ac-SDKP.
Conclusions:
- Cell-matrix adhesion and cell-cell density cooperatively induce HBM apoptosis.
- Biomaterial design can modulate immune cell apoptosis and activation.
- This offers a strategy for creating biomaterials that promote cell adhesion without excessive inflammation.
