scholarly journals Engineering immunomodulatory and osteoinductive implant surfaces via mussel adhesion-mediated ion coordination and molecular clicking

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Tao Wang ◽  
Jiaxiang Bai ◽  
Min Lu ◽  
Chenglong Huang ◽  
Dechun Geng ◽  
...  
Keyword(s):  
Immune Response ◽  
Tissue Repair ◽  
Bone Ingrowth ◽  
M2 Macrophage ◽  
Tissue Formation ◽  
M2 Macrophages ◽  
Dual Effect ◽  
Bone Implant ◽  
Biomedical Interventions

AbstractImmune response and new tissue formation are important aspects of tissue repair. However, only a single aspect is generally considered in previous biomedical interventions, and the synergistic effect is unclear. Here, a dual-effect coating with immobilized immunomodulatory metal ions (e.g., Zn2+) and osteoinductive growth factors (e.g., BMP-2 peptide) is designed via mussel adhesion-mediated ion coordination and molecular clicking strategy. Compared to the bare TiO2 group, Zn2+ can increase M2 macrophage recruitment by up to 92.5% in vivo and upregulate the expression of M2 cytokine IL-10 by 84.5%; while the dual-effect of Zn2+ and BMP-2 peptide can increase M2 macrophages recruitment by up to 124.7% in vivo and upregulate the expression of M2 cytokine IL-10 by 171%. These benefits eventually significantly enhance bone-implant mechanical fixation (203.3 N) and new bone ingrowth (82.1%) compared to the bare TiO2 (98.6 N and 45.1%, respectively). Taken together, the dual-effect coating can be utilized to synergistically modulate the osteoimmune microenvironment at the bone-implant interface, enhancing bone regeneration for successful implantation.

scholarly journals Engineering Immunomodulatory and Osteoinductive Implant Surfaces via Mussel Adhesion-Mediated Ion Coordination and Molecular Clicking

2021 ◽  
Author(s):  
Tao Wang ◽  
Jiaxiang Bai ◽  
Min Lu ◽  
Chenglong Huang ◽  
Dechun Geng ◽  
...  
Keyword(s):  
Tissue Regeneration ◽  
Immunomodulatory Activity ◽  
Tissue Formation ◽  
Surface Adhesion ◽  
Bone Implants ◽  
Dual Effect ◽  
Bone Implant ◽  
New Ideas

Abstract Immune action and new tissue formation are two distinct but overlapping stages involved in tissue regeneration process. However, current biomaterial design is trapped into a one-sided consideration with either focusing on the regulation of immune response or paying attention to induction of new tissue formation. Bone implants also face the same problem. In this work, we designed a dual-effect bone implant with immunomodulatory activity with direct osteogenicity by a mussel adhesion-mediated ion coordination and molecular clicking strategy. The mussel-inspired chemistry for surface adhesion, bioclickable way for molecular conjugation, and coordination means for ion loading led to an immunoactive Zn2+ ion and osteoinductive BMP-2 peptide co-modified coating on bone implants. We demonstrated that the dual-effect coating could better improve cytocompatibility and promote the polarization of macrophages to M2 phenotype in vitro and in vivo. Moreover, the Zn2+ ion and BMP-2 peptide co-modified bone implants showed optimal osteogenicity and osseointegration, thus improving implant stability in vivo. We anticipate this study would provide new ideas and solutions for engineering implants with immunoactivity and tissue inductivity to precisely adapt tissue regeneration microenvironment.

scholarly journals Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yohei Kawai ◽  
Yuji Narita ◽  
Aika Yamawaki-Ogata ◽  
Akihiko Usui ◽  
Kimihiro Komori
Keyword(s):  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Gene Expressions ◽  
Arginase 1 ◽  
M2 Macrophage Polarization

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.

scholarly journals ECT2 overexpression promotes the polarization of tumor-associated macrophages in hepatocellular carcinoma via the ECT2/PLK1/PTEN pathway

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Dafeng Xu ◽  
Yu Wang ◽  
Jincai Wu ◽  
Zhensheng Zhang ◽  
Jiacheng Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Aerobic Glycolysis ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
Integrated Analysis ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Tumor Associated Macrophages ◽  
In Vivo Experiments

AbstractHepatocellular carcinoma (HCC) is a common high-mortality cancer, mainly due to diagnostic difficulties during its early clinical stages. In this study, we aimed to identify genes that are important for HCC diagnosis and treatment, and we investigated the underlying mechanism of prognostic differences. Differentially expressed genes (DEGs) were identified by using the limma package, and receiver operating characteristic curve analysis was performed to identify diagnostic markers for HCC. Bioinformatics and clinical specimens were used to assess epithelial cell transforming 2 (ECT2) in terms of expression, prognostic value, pathways, and immune correlations. In vitro experiments were used to investigate the underlying mechanism and function of ECT2, and the results were confirmed through in vivo experiments. The integrated analysis revealed 53 upregulated DEGs, and one candidate biomarker for diagnosis (ECT2) was detected. High expression of ECT2 was found to be an independent prognostic risk factor for HCC. ECT2 expression showed a strong correlation with tumor-associated macrophages. We found that ECT2 overexpression increased the migration and proliferation of HCC cells. It also promoted the expression of PLK1, which subsequently interacted with PTEN and interfered with its nuclear translocation, ultimately enhancing aerobic glycolysis and promoting M2 macrophage polarization. M2 macrophages suppress the functions of NK cells and T cells, and this was confirmed in the in vivo experiments. Overall, ECT2 may promote the polarization of M2 macrophages by enhancing aerobic glycolysis and suppressing the functions of immune cells. ECT2 could serve as a candidate diagnostic and prognostic biomarker for HCC.

scholarly journals microRNA-21-5p from M2 macrophage-derived extracellular vesicles promotes the differentiation and activity of pancreatic cancer stem cells by mediating KLF3

2021 ◽  
Author(s):  
Jian Chang ◽  
Hanjun Li ◽  
Zhongchao Zhu ◽  
Pei Mei ◽  
Weimin Hu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Extracellular Vesicles ◽  
Stem Cell Differentiation ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Invasion And Migration ◽  
Oct4 Expression

Abstract Aim Given the fact that tumor-associated macrophage-derived extracellular vesicles (EVs) are attributable to tumor aggressiveness, this research intends to decode the mechanism of M2 macrophage-derived EVs in the differentiation and activities of pancreatic cancer (PaCa) stem cells via delivering microRNA (miR)-21-5p. Methods Polarized M2 macrophages were induced, from which EVs were collected and identified. miR-21-5p expression in M2 macrophage-derived EVs was tested. After cell sorting, CD24+CD44+EpCAM+ stem cells were co-cultured with M2 macrophages, in which miR-21-5p was upregulated or downregulated. The effects of M2 macrophage-derived EVs and miR-21-5p on Nanog/octamer-binding transcription factor 4 (Oct4) expression, sphere formation, colony formation, invasion and migration capacities, apoptosis, and in vivo tumorigenic ability were examined. Krüppel-like factor 3 (KLF3) expression and its interaction with miR-21-5p were determined. Results M2 macrophage-derived EVs promoted PaCa stem cell differentiation and activities. miR-21a-5p was upregulated in M2 macrophage-derived EVs. miR-21a-5p downregulation in M2 macrophage-derived EVs inhibited Nanog/Oct4 expression and impaired sphere-forming, colony-forming, invasion, migration, and anti-apoptosis abilities of PaCa stem cells in vitro and tumorigenic ability in vivo. miR-21-5p targeted KLF3 to mediate the differentiation and activities of PaCa stem cells, and KLF3 was downregulated in PaCa stem cells. Conclusion This work explains that M2 macrophage-derived exosomal miR-21a-5p stimulates differentiation and activity of PaCa stem cells via targeting KLF3, paving a novel way for attenuating PaCa stemness. Graphical abstract

scholarly journals Exosomes Derived from M2 Macrophages Exert a Therapeutic Effect via Inhibition of the PI3K/AKT/mTOR Pathway in Rats with Knee Osteoarthritic

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Zha Xi Da-wa ◽  
Ma Jun ◽  
Liu Chao-Zheng ◽  
Yang Sen-Lin ◽  
Lu Chuan ◽  
...  
Keyword(s):  
Tissue Repair ◽  
Membrane Vesicles ◽  
Bilayer Membrane ◽  
M2 Macrophage ◽  
Protective Effects ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Novel Approach ◽  
Transmission Electron ◽  
Stimulation Of

Macrophages are commonly classified as M1 macrophages or M2 macrophages. M2 macrophages are obtained by stimulation of IL-4 with anti-inflammatory and tissue repair effects. Exosomes are 30–150 nm lipid bilayer membrane vesicles derived from most living cells and have a variety of biological functions. Previous studies have shown that macrophage exosomes can influence the course of some autoimmune diseases, but their effect on knee osteoarthritis (KOA) has not been reported. Here, we analyze the roles of exosomes derived from M2 macrophage phenotypes in KOA rats. Exosomes were isolated from the supernatant of M2 macrophages and identified via transmission electron microscopy (TEM), Western blotting, and DLS. The results showed that M2 macrophage exosomes significantly attenuated the inflammatory response and pathological damage of articular cartilage in KOA rats. In addition, a key protein associated with KOA including Aggrecan, Col-10, SOX6, and Runx2 was significantly increased, while MMP-13 was significantly suppressed following treatment with M2 macrophage exosomes. The present study indicated that M2 macrophage exosomes exerted protective effects on KOA rats mainly mediated by the PI3K/AKT/mTOR signal pathway. These findings provide a novel approach for the treatment of KOA.

scholarly journals Generation of novel diagnostic and therapeutic exosomes to detect and deplete pro-tumorigenic M2-macrophages

2019 ◽  
Author(s):  
Mohammad Harun Rashid ◽  
Thaiz F. Borin ◽  
Roxan Ara ◽  
Ahmet Alptekin ◽  
Yutao Liu ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Ex Vivo ◽  
Fluorescent Microscopy ◽  
Metastatic Breast ◽  
M2 Macrophage ◽  
Similar Distribution ◽  
M2 Macrophages ◽  
Microscopy Imaging

AbstractGiven their pro-tumorigenic function and prevalence in most malignant tumors with lower survival, early detection and intervention of CD206-positive M2-macrophages may boost the clinical outcome. To determine in vivo distribution of M2-macrophages, we adopted 111In-oxine-based radiolabeling of the targeted exosomes. When injected these radiolabeled targeted exosomes into breast tumor-bearing mice, exosomes accumulated at the periphery of the primary tumor, metastatic foci in the lungs, spleen, and liver. Ex vivo quantification of radioactivity also showed similar distribution. Injected DiI dye-labeled exosomes into the same mice showed adherence of exosomes to the CD206-positive M2-macrophages on ex vivo fluorescent microscopy imaging. In addition, we utilized these engineered exosomes to carry the Fc portion of IgG2b with the intention of augmenting antibody-dependent cell-mediated cytotoxicity. We have auspiciously demonstrated that M2-macrophage targeting therapeutic exosomes deplete M2-macrophages both in vitro and in vivo, and reduce tumor burden increasing survival in a metastatic breast cancer model.

scholarly journals Long Non-Coding RNA PCAT6 Induces M2 Polarization of Macrophages in Cholangiocarcinoma via Modulating miR-326 and RhoA-ROCK Signaling Pathway

2021 ◽  
Vol 10 ◽  
Author(s):  
Jianfei Tu ◽  
Fazong Wu ◽  
Li Chen ◽  
Liyun Zheng ◽  
Yang Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Function ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
M2 Macrophage ◽  
Metabolic Dysfunction ◽  
Downstream Target ◽  
M2 Polarization

LncRNAs can act crucial roles in multiple tumors including cholangiocarcinoma (CCA). M2 polarization of macrophages is crucial for their biological roles in immunologic tolerance, which is able to induce tumorigenesis. Given that increasing evidence have suggested that lncRNAs could participate in modulating immune cell differentiation and function. Our current study was aimed to identify the underlying mechanism of lncRNA prostate cancer-associated transcript 6 (PCAT6) in CCA progression via regulating M2 macrophage polarization. PCAT6 has been reported as an oncogene in many cancers. In our work, we observed increased expression of PCAT6 in CCA patients. PCAT6 expression in various types of immune cells derived from CCA patients was tested by quantitative real-time PCR (qRT-PCR). It was revealed that PCAT6 was highly expressed in macrophages, which indicated that PCAT6 might regulate the function of macrophages to promote CCA progression. Then, via establishing CCA xenograft mouse model, we found loss of PCAT6 obviously triggered the immune response and reduced the in vivo tumor growth. In addition, overexpression of PCAT6 led to the M2 polarization of THP-1-differentiated macrophages. Moreover, miR-326 was predicted and proved as a target for PCAT6. In addition, down-regulation of PCAT6 repressed M2 polarization of macrophages, which was reversed by miR-326 inhibitors. The increase of PCAT6 induced the accumulation of ROS, mitochondrial and metabolic dysfunction in macrophages and mimics of miR-326 exhibited an opposite process. RohA has been recognized as a significant regulator of immune cell function. In our current work, we observed that RohA function as a downstream target for miR-326. In conclusion, our study highlighted a significant role of PCAT6/miR-326/RohA in immune response of macrophages in CCA and indicated PCAT6 as a potential target of immunotherapy in CCA.

scholarly journals Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages

2020 ◽  
Author(s):  
Claire E. Witherel ◽  
Kimheak Sao ◽  
Becky K. Brisson ◽  
Biao Han ◽  
Susan W. Volk ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Foreign Body ◽  
Dermal Fibroblasts ◽  
Foreign Body Response ◽  
Conditioned Media ◽  
Proper Function ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Body Response

AbstractAberrant extracellular matrix (ECM) assembly surrounding implanted biomaterials is the hallmark of the foreign body response, in which implants become encapsulated in thick fibrous tissue that prevents their proper function. While macrophages are known regulators of fibroblast behavior, how their phenotype influences ECM assembly and the progression of the foreign body response is poorly understood. In this study, we used in vitro models with physiologically relevant macrophage phenotypes, as well as controlled release of macrophage-modulating cytokines from gelatin hydrogels implanted subcutaneously in vivo to investigate the role of macrophages in ECM assembly. Primary human macrophages were polarized to four distinct phenotypes, which have each been associated with fibrosis, including pro-inflammatory M1, pro-healing M2, and a hybrid M1/M2, generated by exposing macrophages to M1- and M2-promoting stimuli simultaneously. Additionally, macrophages were first polarized to M1 and then to M2 (M1→M2) to generate a phenotype typically observed during normal wound healing. Human dermal fibroblasts that were cultured in macrophage-conditioned media upregulated numerous genes involved in regulation of ECM assembly, especially in M2-conditioned media. Hybrid M1/M2 macrophage-conditioned media caused fibroblasts to produce a matrix with thicker and less aligned fibers, while M2 macrophage-conditioned media caused the formation of a more aligned matrix with thinner fibers. Gelatin methacrylate hydrogels containing interleukin-4 (IL4) and IL13-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were designed to promote the M2 phenotype in a murine subcutaneous in vivo model. NanoString multiplex gene expression analysis of hydrogel explants showed that hydrogels with and without drug caused markers of both M1 and M2 phenotypes to be highly expressed, but the release of IL4+IL13 promoted upregulation of M2 markers and genes associated with regulation of ECM assembly, such as Col5a1 and Col6a1. Biochemical analysis and second harmonic generation microscopy showed that the release of IL4+IL13 increased total sulfated glycosaminoglycan content and decreased fibril alignment, which is typically associated with less fibrotic tissue. Together, these results show that hybrid M1/M2 macrophages regulate ECM assembly, and that shifting the balance towards M2 may promote architectural and compositional changes in ECM with enhanced potential for downstream remodeling.

scholarly journals Mucin hydrogel glyco-modulation to investigate immune activity of mucin glycans

2019 ◽  
Author(s):  
Hongji Yan ◽  
Morgan Hjorth ◽  
Benjamin Winkeljann ◽  
Illia Dobryden ◽  
Oliver Lieleg ◽  
...  
Keyword(s):  
Immune Response ◽  
Sialic Acid ◽  
Biomedical Applications ◽  
Macrophage Activation ◽  
Building Blocks ◽  
M2 Macrophage ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes

AbstractMucins are multifunctional glycosylated proteins that are increasingly investigated as building blocks of novel biomaterials. Once assembled into hydrogels (Muc gels), mucins were shown to modulate the recruitment and activation of immune cells and avoid fibrous encapsulation in vivo. However, nothing is known about the early immune response to Muc gels. This study characterizes the response of macrophages, important orchestrators of the material-mediated immune response, over the first 7 days in contact with Muc gels. The role of mucin-bound sialic acid sugar residues was investigated by first enzymatically cleaving the sugar, then assembling the mucin variants into covalently crosslinked hydrogels with rheological and surface nanomechanical properties similar to non-modified Muc gels. Results with THP1 and human primary peripheral blood monocytes-derived macrophages were strikingly consistent and showed that Muc gels transiently activate the expression of both pro-inflammatory and anti-inflammatory cytokines and cell surface markers, with a maximum on the first day and loss of the effect after 7 days. The activation was sialic acid-dependent for a majority of the markers followed. The pattern of gene expression, protein expression, and functional measurements did not strictly correspond to M1 or M2 macrophage phenotypes. This study highlights the complex early events in macrophage activation in contact with mucin materials and the importance of sialic acid residues in such a response. The enzymatic glyco-modulation of Muc gels appears as a useful tool to help understand the biological functions of specific glycans on mucins which can further inform on their use in various biomedical applications.

scholarly journals Mast Cells Contribute to the Immunomodulatory Effect of the Biomaterial Microenvironment in a Gender Specific Manner

2020 ◽  
Author(s):  
Raymond M. Wang ◽  
Jessica Ungerleider ◽  
Yu Kawakami ◽  
Yuko Kawakami ◽  
Toshiaki Kawakami ◽  
...  
Keyword(s):  
Immune Response ◽  
Mast Cell ◽  
Mast Cells ◽  
Tissue Repair ◽  
M2 Macrophage ◽  
Male Response ◽  
Specific Manner ◽  
Biomaterial Scaffolds ◽  
Gender Specific ◽  
Deficient Mice

AbstractRegulation of the immune response contributes to the severity and outcomes in various disease conditions. Bioactive immunomodulatory biomaterials have shown promise for influencing these responses to promote tissue repair and regeneration. In this study, we investigated the role of mast cells in the regulation of the immune response to biomaterial scaffolds. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a gender specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with mast cell adoptive transfer. Further investigation of the later stage immune response in male mice determined a sustained pro-inflammatory gene expression profile in deficient mice consisting of members from the IL-1 cytokine family and related downstream pathways. As mast cells were mainly associated with detrimental pro-inflammatory outcomes for biomaterial scaffolds, these results demonstrate their contribution to induced immunomodulatory therapies and support their potential as a critical immune regulatory element that can be manipulated for stimulating endogenous tissue repair.

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