Substrate stiffness modulates bone marrow-derived macrophage polarization through NF-κB signaling pathway

Chen, Mimi; Zhang, Yu; Zhou, Pinghui; Liu, Xingzhi; Zhao, Huan; Zhou, Xichao; Gu, Qianqun; Li, Bin; Zhu, Xuesong; Shi, Qin

doi:10.1016/j.bioactmat.2020.05.004

Cited by 127 publications

(98 citation statements)

References 49 publications

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“…We also show that Piezo1 plays a role in sensing environmental stiffness in macrophages. Stiff substrates have been shown to promote macrophage inflammatory activation through MyD88-dependent pathways and enhanced NFκB activation 9 , 58 , but the role of stiffness in regulating healing activation has been less clear. We demonstrate stiffness-dependent increases in Ca 2+ influx in response to the Piezo1 agonist Yoda1 and IFNγ/LPS stimulation.…”

Section: Discussionmentioning

confidence: 99%

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

et al. 2021

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Macrophages perform diverse functions within tissues during immune responses to pathogens and injury, but molecular mechanisms by which physical properties of the tissue regulate macrophage behavior are less well understood. Here, we examine the role of the mechanically activated cation channel Piezo1 in macrophage polarization and sensing of microenvironmental stiffness. We show that macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Additionally, macrophages expressing the transgenic Ca2+ reporter, Salsa6f, reveal that Ca2+ influx is dependent on Piezo1, modulated by soluble signals, and enhanced on stiff substrates. Furthermore, stiffness-dependent changes in macrophage function, both in vitro and in response to subcutaneous implantation of biomaterials in vivo, require Piezo1. Finally, we show that positive feedback between Piezo1 and actin drives macrophage activation. Together, our studies reveal that Piezo1 is a mechanosensor of stiffness in macrophages, and that its activity modulates polarization responses.

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Section: Discussionmentioning

confidence: 99%

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

et al. 2021

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“…For bone regeneration biomaterials, another issue of concern is that an acceptable immunoinflammatory response induced by biomaterials plays a vital role in realizing the tissue repair process [ 60 ]. It is an important strategy to use the functional phenotypes of macrophages activated by biomaterials to assess the regenerative and immunoregulatory potential of biomaterials [ 7 , 61 , 62 ]. Based on the phenotypical and functional stability of the RAW264.7 murine macrophage line [ 63 , 64 ], an inflammatory model was established by activating RAW264.7 cells with 1 μg/ml lipopolysaccharide to preliminarily evaluate the immunoinflammatory properties of the ECM-based scaffolds.…”

Section: Discussionmentioning

confidence: 99%

Effect of cyclic mechanical loading on immunoinflammatory microenvironment in biofabricating hydroxyapatite scaffold for bone regeneration

Zhang

Liu

Guo

et al. 2021

Bioactive Materials

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It has been proven that the mechanical microenvironment can impact the differentiation of mesenchymal stem cells (MSCs). However, the effect of mechanical stimuli in biofabricating hydroxyapatite scaffolds on the inflammatory response of MSCs remains unclear. This study aimed to investigate the effect of mechanical loading on the inflammatory response of MSCs seeded on scaffolds. Cyclic mechanical loading was applied to biofabricate the cell-scaffold composite for 15 min/day over 7, 14, or 21 days. At the predetermined time points, culture supernatant was collected for inflammatory mediator detection, and gene expression was analyzed by qRT-PCR. The results showed that the expression of inflammatory mediators ( IL1B and IL8) was downregulated ( p < 0.05) and the expression of ALP ( p < 0.01) and COL1A1 ( p < 0.05) was upregulated under mechanical loading. The cell-scaffold composites biofabricated with or without mechanical loading were freeze-dried to prepare extracellular matrix-based scaffolds (ECM-based scaffolds). Murine macrophages were seeded on the ECM-based scaffolds to evaluate their polarization. The ECM-based scaffolds that were biofabricated with mechanical loading before freeze-drying enhanced the expression of M2 polarization-related biomarkers ( Arginase 1 and Mrc1 , p < 0.05) of macrophages in vitro and increased bone volume/total volume ratio in vivo. Overall, these findings demonstrated that mechanical loading could dually modulate the inflammatory responses and osteogenic differentiation of MSCs. Besides, the ECM-based scaffolds that were biofabricated with mechanical loading before freeze-drying facilitated the M2 polarization of macrophages in vitro and bone regeneration in vivo. Mechanical loading may be a promising biofabrication strategy for bone biomaterials.

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“…41 However, in a similar study, the use of polyacrylamide hydrogels showed that increased stiffness enhances M2 polarization by modulating reactive oxygen species (ROS)-mediated NF-κB signaling. 42 Mechanistically, Wnt/β-catenin signaling 43 and MAPK signaling 44,45 have also shown to play a role in macrophage responses to high-stiffness biomaterials.…”

Section: Role Of Surface Topographymentioning

confidence: 99%

Modulation of immune-inflammatory responses through surface modifications of biomaterials to promote bone healing and regeneration

et al. 2021

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Control of inflammation is indispensable for optimal oral wound healing and tissue regeneration. Several biomaterials have been used to enhance the regenerative outcomes; however, the biomaterial implantation can ensure an immune-inflammatory response. The interface between the cells and the biomaterial surface plays a critical role in determining the success of soft and hard tissue regeneration. The initial inflammatory response upon biomaterial implantation helps in tissue repair and regeneration, however, persistant inflammation impairs the wound healing response. The cells interact with the biomaterials through extracellular matrix proteins leading to protein adsorption followed by recruitment, attachment, migration, and proliferation of several immune-inflammatory cells. Physical nanotopography of biomaterials, such as surface proteins, roughness, and porosity, is crucial for driving cellular attachment and migration. Similarly, modification of scaffold surface chemistry by adapting hydrophilicity, surface charge, surface coatings, can down-regulate the initiation of pro-inflammatory cascades. Besides, functionalization of scaffold surfaces with active biological molecules can down-regulate pro-inflammatory and pro-resorptive mediators’ release as well as actively up-regulate anti-inflammatory markers. This review encompasses various strategies for the optimization of physical, chemical, and biological properties of biomaterial and the underlying mechanisms to modulate the immune-inflammatory response, thereby, promoting the tissue integration and subsequent soft and hard tissue regeneration potential of the administered biomaterial.

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Substrate stiffness modulates bone marrow-derived macrophage polarization through NF-κB signaling pathway

Cited by 127 publications

References 49 publications

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

Mechanically activated ion channel Piezo1 modulates macrophage polarization and stiffness sensing

Effect of cyclic mechanical loading on immunoinflammatory microenvironment in biofabricating hydroxyapatite scaffold for bone regeneration

Modulation of immune-inflammatory responses through surface modifications of biomaterials to promote bone healing and regeneration

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