Insufficient activation or over-activation of T cells due to the dendritic cells (DCs) state can cause negative effects on immunotherapy, making it crucial for DCs to maintain different states in different treatments. Polysaccharides are one of the most studied substances to promote DCs maturation. However, in many methods, optimizing the spatial dimension of the interaction between polysaccharides and cells is often overlooked. Therefore, in this study, a new strategy from the perspective of spatial dimension is proposed to regulate the efficacy of polysaccharides in promoting DCs maturation. An anchoring molecule (DMA) is introduced to existing glycopolymers for the confinement effect, and the effect can be turned off by oxidation of DMA. Among the prepared on-confined (PMD2 ), off-confined (PMD2 -O), and norm (PM2 ) glycopolymers, PMD2 and PMD2 -O show the best and worst results, respectively, in terms of the amount of binding to DCs and the effect on promoting DCs maturation. This sufficiently shows that the turn-on and off of confinement effect can regulate the maturation of DCs by polysaccharides. Based on the all-atom molecular dynamics (MD) simulation, the mechanism of difference in the confinement effect is explained. This simple method can also be used to regulate other molecule-cell interactions to guide cell behavior.
Immunotherapy , T-Lymphocytes , Cell Differentiation , Polysaccharides , Dendritic Cells/metabolism
Cancer cell migration is one of the most important processes in cancer metastasis. Metastasis is the major cause of death from most solid tumors; therefore, suppressing cancer cell migration is an important means of reducing cancer mortality. Cell surface engineering can alter the interactions between cells and their microenvironment, thereby offering an effective method of controlling the migration of the cells. This paper reports that modification of the mouse melanoma (B16) cancer cell surface with glycopolymers affects the migration of the cells. Changes in cell morphology, migratory trajectories, and velocity were investigated by time-lapse cell tracking. The data showed that the migration direction is altered and diffusion slows down for modified B16 cells compared to unmodified B16 cells. When modified and unmodified B16 cells were mixed, wound-healing experiments and particle image velocimetry (PIV) analysis showed that the collective migration of unmodified B16 cells was suppressed because of vortexlike motions induced by the modified cells. The work demonstrates the important role of surface properties/modification in cancer cell migration, thereby providing new insights relative to the treatment of cancer metastasis.
Antineoplastic Agents/pharmacology , Biocompatible Materials/pharmacology , Melanoma, Experimental/drug therapy , Polymers/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biocompatible Materials/chemical synthesis , Biocompatible Materials/chemistry , Cell Line, Tumor , Cell Movement/drug effects , Drug Screening Assays, Antitumor , Materials Testing , Melanoma, Experimental/pathology , Mice , Particle Size , Polymers/chemical synthesis , Polymers/chemistry , Surface Properties
Stem cell fate is determined by specific niches that provide multiple physical, chemical, and biological cues. However, the hierarchy or cascade of impact of these cues remains elusive due to their spatiotemporal complexity. Here, anisotropic silk protein nanofiber-based hydrogels with suitable cell adhesion capacity are developed to mimic the physical microenvironment inside the blastocele. The hydrogels enable mouse embryonic stem cells (mESCs) to maintain stemness in vitro in the absence of both leukemia inhibitory factor (LIF) and mouse embryonic fibroblasts (MEFs), two critical factors in the standard protocol for mESC maintenance. The mESCs on hydrogels can achieve superior pluripotency, genetic stability, developmental capacity, and germline transmission to those cultured with the standard protocol. Such biomaterials establish an improved dynamic niche through stimulating the secretion of autocrine factors and are sufficient to maintain the pluripotency and propagation of ESCs. The mESCs on hydrogels are distinct in their expression profiles and more resemble ESCs in vivo. The physical cues can thus initiate a self-sustaining stemness-maintaining program. In addition to providing a relatively simple and low-cost option for expansion and utility of ESCs in biological research and therapeutic applications, this biomimetic material helps gain more insights into the underpinnings of early mammalian embryogenesis.
Hydrogels , Mouse Embryonic Stem Cells , Animals , Fibroblasts , Mice
Glycopolymer-based drugs for immunotherapy have attracted increasing attention because the affinity between glycans and proteins plays an important role in immune responses. Previous studies indicate that the polymer chain length influences the affinity. In the studies on enhancing the immune response by glycans, it is found that both oligosaccharides and long-chain glycopolymers work well. However, there is a lack of systematic studies on the immune enhancement effect and the binding ability of oligomers and polymers to immune-related proteins. In this paper, to study the influence of the chain length, glycopolymers based on N-acetylglucosamine with different chain lengths were synthesized, and their interaction with immune-related proteins and their effect on dendritic cell maturation were evaluated. It was proved that compared with l-glycopolymers (degree of polymerization (DP) > 20), s-glycopolymers (DP < 20) showed better binding ability to the dendritic cell-specific ICAM-3-grabbing nonintegrin protein and the toll-like receptor 4 and myeloid differentiation factor 2 complex protein by quartz crystal microbalance and molecular docking simulation. When the total sugar unit amounts are equal, s-glycopolymers are proved to be superior in promoting dendritic cell maturation by detecting the expression level of CD80 and CD86 on the surface of dendritic cells. Through the combination of experimental characterization and theoretical simulation, a deep look into the interaction between immune-related proteins and glycopolymers with different chain lengths is helpful to improve the understanding of the immune-related interactions and provides a good theoretical basis for the design of new glycopolymer-based immune drugs.
Cell Adhesion Molecules/metabolism , Lectins, C-Type/metabolism , Lymphocyte Antigen 96/metabolism , Polymethacrylic Acids/pharmacology , Receptors, Cell Surface/metabolism , Toll-Like Receptor 4/metabolism , Animals , Cell Line , Dendritic Cells/drug effects , Glucosamine/analogs & derivatives , Glucosamine/metabolism , Glucosamine/pharmacology , Glucosamine/toxicity , Ligands , Mice , Molecular Docking Simulation , Molecular Structure , Polymethacrylic Acids/chemistry , Polymethacrylic Acids/metabolism , Polymethacrylic Acids/toxicity , Protein Binding
Dendritic cell (DC) modification to enhance antigen presentation is a valuable strategy in cancer immune therapy. Other than focusing on regulating interactions between DC and antigens, we intend to promote cell interactions between DC and T cell by cell surface engineering. T cell activation is greatly improved and generates higher tumor toxicity with the aid of the synthetic glycopolymer modified on the DC surface, although the glycopolymer alone shows no effect. The great promotion of DC-T cell attraction is revealed by cell image tracking in terms of both frequency and duration of contacts. Our findings provide a new method of T cell activation by these engineered "sweet DCs." This strategy is beneficial for developing more efficient DC-based vaccines.
Identifying probiotics and pathogens is of great interest to the health of the human body. It is critical to develop microbiota-targeted therapies to have high specificity including strain specificity. In this study, we have utilized E. coli MG1655 bacteria as living templates to synthesize glycopolymers in situ with high selectivity. By this bacteria-sugar monomer-aptation-polymerization (BS-MAP) method, we have obtained glycopolymers from the surface of bacteria which can recognize template bacteria from two strains of E. coli and the specific bacteria-binding ability of glycopolymers was confirmed by both bacterial aggregation experiment and QCM-D measurements. Furthermore, the synthesized glycopolymers have shown a powerful inhibitory ability which can prevent bacteria from harming cells in both anti-infection and co-culture tests.
Physically crosslinked hydrogels were synthesized by copolymerization of acrylamide and acrylic acid monomers in the presence of cationic polyelectrolyte polydimethyldiallylammonium chloride. The fully physically crosslinked hydrogel showed good mechanical properties and good adhesion with a variety of substrates. These advantages can be attributed to the homogeneous distribution of crosslinking points due to hierarchical hydrogen bonds and electrostatic attractions in the hydrogel networks. Furthermore, these non-covalent bonds provided an effective pathway to dissipate energy. The mechanical properties of the hydrogels can be easily tuned by changing the chemical composition and ratio of monomers. We further showed that the transparent hydrogels were cytocompatible, and can be used for biomedical applications, including pH-triggered small molecule delivery and hydrogel-based hybrids for detecting doses of radiotherapy.
