Macrophage activation determines the fate of biomaterials implantation. Though researches have shown that fibronectin (FN) is highly involved in integrin-induced macrophage activation on biomaterials, the mechanism of how nanosized structure affects macrophage behavior is still unknown. Here, titanium dioxide nanotube structures with different sizes are fabricated to investigate the effects of nanostructure on macrophage activation. Compared with larger sized nanotubes and smooth surface, 30 nm nanotubes exhibit considerable lesser pro-inflammatory properties on macrophage differentiation. Confocal protein observation and molecular dynamics simulation show that FN displays conformation changes on different nanotubes in a feature of "size-confined," which causes the hiding of Arg-Gly-Asp (RGD) domain on other surfaces. The matching size of nanotube with FN allows the maximum exposure of RGD on 30 nm nanotubes, activating integrin-mediated focal adhesion kinase (FAK)-phosphatidylinositol-3 kinase 𝜸 (PI3K𝜸) pathway to inhibit nuclear factor kappa B (NF-𝜿B) signaling. In conclusion, this study explains the mechanism of nanostructural-biological signaling transduction in protein and molecular levels, as well as proposes a promising strategy for surface modification to regulate immune responses on bioimplants.
Mitochondria are the powerhouse of eukaryotic cells, which regulate cell metabolism and differentiation. Recently, mitochondrial transfer between cells has been shown to direct recipient cell fate. However, it is unclear whether mitochondria can translocate to stem cells and whether this transfer alters stem cell fate. Here, mesenchymal stem cell (MSC) regulation is examined by macrophages in the bone marrow environment. It is found that macrophages promote osteogenic differentiation of MSCs by delivering mitochondria to MSCs. However, under osteoporotic conditions, macrophages with altered phenotypes, and metabolic statuses release oxidatively damaged mitochondria. Increased mitochondrial transfer of M1-like macrophages to MSCs triggers a reactive oxygen species burst, which leads to metabolic remodeling. It is showed that abnormal metabolism in MSCs is caused by the abnormal succinate accumulation, which is a key factor in abnormal osteogenic differentiation. These results reveal that mitochondrial transfer from macrophages to MSCs allows metabolic crosstalk to regulate bone homeostasis. This mechanism identifies a potential target for the treatment of osteoporosis.
With the rapid development of nanotechnology, nanoparticles (NPs) are widely used in all fields of life. Nowadays, NPs have shown extraordinary antimicrobial activities and become one of the most popular strategies to combat antibiotic resistance. Whether they are equally effective in combating bacterial persistence, another important reason leading to antibiotic treatment failure, remains unknown. Persister cells are a small subgroup of phenotypic drug‐tolerant cells in an isogenic bacterial population. Here, various types of NPs are used in combination with different antibiotics to destroy persisters. Strikingly, rather than eradicating persister cells, a wide range of NPs promote the formation of bacterial persistence. It is uncovered by PCR, thermogravimetric analysis, intracellular potassium ion staining, and molecular dynamics simulation that the persister promotion effect is achieved through exerting a hyperosmotic pressure around the cells. Moreover, protein mass spectrometry, fluorescence microscope images, and SDS‐PAGE indicate NPs can further hijack cell osmotic regulatory circuits by inducing aggregation of outer membrane protein OmpA and OmpC. These findings question the efficacy of using NPs as antimicrobial agents and raise the possibility that widely used NPs may facilitate the global emergence of bacterial antibiotic tolerance.
Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.
The entry of implants triggers the secretion of damage associated molecular patterns (DAMPs) that recruit dendritic cells (DCs) and results in subsequent foreign body reaction (FBR). Though several studies have illustrated that the surface accessible area (SAA) of implants plays a key role in the process of DAMPs release and absorption, the effect of SAA on the immune reaction still remains unknown. Here, a series of TiO 2 plates with different SAA is fabricated to investigate the relationship between SAA and FBR. Compared with larger SAA surface, the aggregation of DC is significantly inhibited by lower SAA surface. Total internal reflection microscopy (TIRFM) and molecular dynamic (MD) simulation show that although high mobility group box 1 (HMGB1) is adsorbed more on plates with lower SAA, the exposure ratio of cysteine (CYS) residue in HMGB1 is significantly decreased in lower SAA group. The lower exposure of CYS reduces the activation of Toll-like receptors 4 (TLR4), which down-regulates the expression of myeloid differentiation factor (Myd88)-TNF receptor associated factor 6 (TRAF6) to inhibit nuclear factor kappa B (NF-𝜿B) signaling. Generally, this study reveals the mechanism of how SAA, a nanoscale property, affects FBR from perspective of DAMPs, and provides a new direction for designing better biocompatible implants.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.