Sequential activation of heterogeneous macrophage phenotypes is essential for biomaterials-induced bone regeneration

Qiao, Wei; Xie, Hujun; Fang, Jinghan; Shen, Jie; Li, Wenting; Shen, Danni; Wu, Jun; Wu, Shuilin; Liu, Xuanyong; Zheng, Yufeng; Cheung, Kenneth M.C.; Yeung, K.W.K.

doi:10.1016/j.biomaterials.2021.121038

Cited by 76 publications

(52 citation statements)

References 78 publications

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“…Notably, iron promotes M1 macrophage polarization under a certain type of conditions ( 5 , 16 , 19 , 20 ); on the contrary, iron also promotes M2 polarization ( 21 ). These paradoxical findings reveal that macrophage showed heterogeneous phenotypes and dynamic populations ( 22 , 23 ).…”

Section: Iron Regulates Macrophage Polarizationmentioning

confidence: 99%

Iron Metabolism and Immune Regulation

et al. 2022

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Iron is a critical element for living cells in terrestrial life. Although iron metabolism is strictly controlled in the body, disturbance of iron homeostasis under certain type of condition leads to innate and adaptive immune response. In innate immunity, iron regulates macrophage polarizations, neutrophils recruitment, and NK cells activity. In adaptive immunity, iron had an effect on the activation and differentiation of Th1, Th2, and Th17 and CTL, and antibody response in B cells. In this review, we focused on iron and immune regulation and listed the specific role of iron in macrophage polarization, T-cell activation, and B-cells antibody response. In addition, correlations between iron and several diseases such as cancer and aging degenerative diseases and some therapeutic strategies targeting those diseases are also discussed.

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Section: Iron Regulates Macrophage Polarizationmentioning

confidence: 99%

Iron Metabolism and Immune Regulation

et al. 2022

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“…Drawing inspiration from mussel adhesive proteins that contain 3,4-dihydroxy-L-phenylalanine (L-DOPA), the as-prepared HS substrates were coated in a biomimetic fashion with PDA, causing the surface to become more versatile and functional. The introduction of PDA coating also proved to be helpful for cell adhesion and proliferation 28 . Nevertheless, this coating still lacks strong therapeutic functions to control osteogenesis and osteoclastogenesis, which greatly impedes its potential application in bone scaffolds.…”

Section: Resultsmentioning

confidence: 99%

“…This phenomenon was mainly attributed to the introduction of PDA coating and HA, which is in line with previous work reporting the positive role of PDA and HA dually functionalized biomaterials on surface wettability 37 – 39 . The enhancement of surface hydrophilicity was proven to enable a profound effect on initial inflammation and subsequent biological performance between the implant surface and host surrounding tissue, including cell adhesion, proliferation, differentiation, and the formation of new bone and blood vessels 28 , 38 . Collectively, the combination of a 3D macroporous structure, PDA-mediated immobilization of LYN and HA, nanoroughened surface topography, and improved hydrophilicity made HS@PDA-LYN/HA more likely to exhibit a beneficial effect on promoting bone regeneration both in vitro and in vivo.…”

Section: Resultsmentioning

confidence: 99%

Mussel-inspired multifunctional surface through promoting osteogenesis and inhibiting osteoclastogenesis to facilitate bone regeneration

Zhang

et al. 2022

npj Regen Med

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Osteogenesis and osteoclastogenesis are closely associated during the bone regeneration process. The development of multifunctional bone repair scaffolds with dual therapeutic actions (pro-osteogenesis and anti-osteoclastogenesis) is still a challenging task for bone tissue engineering applications. Herein, through a facile surface coating process, mussel-inspired polydopamine (PDA) is adhered to the surface of a biocompatible porous scaffold followed by the immobilization of a small-molecule activator (LYN-1604 (LYN)) and the subsequent in situ coprecipitation of hydroxyapatite (HA) nanocrystals. PDA, acting as an intermediate bridge, can provide strong LYN immobilization and biomineralization ability, while LYN targets osteoclast precursor cells to inhibit osteoclastic differentiation and functional activity, which endows LYN/HA-coated hybrid scaffolds with robust anti-osteoclastogenesis ability. Due to the synergistic effects of the LYN and HA components, the obtained three-dimensional hybrid scaffolds exhibited the dual effects of osteoclastic inhibition and osteogenic stimulation, thereby promoting bone tissue repair. Systematic characterization experiments confirmed the successful fabrication of LYN/HA-coated hybrid scaffolds, which exhibited an interconnected porous structure with nanoroughened surface topography, favorable hydrophilicity, and improved mechanical properties, as well as the sustained sequential release of LYN and Ca ions. In vitro experiments demonstrated that LYN/HA-coated hybrid scaffolds possessed satisfactory cytocompatibility, effectively promoting cell adhesion, spreading, proliferation, alkaline phosphatase activity, matrix mineralization, and osteogenesis-related gene and protein secretion, as well as stimulating angiogenic differentiation of endothelial cells. In addition to osteogenesis, the engineered scaffolds also significantly reduced osteoclastogenesis, such as tartrate-resistant acid phosphatase activity, F-actin ring staining, and osteoclastogenesis-related gene and protein secretion. More importantly, in a rat calvarial defect model, the newly developed hybrid scaffolds significantly promoted bone repair and regeneration. Microcomputed tomography, histological, and immunohistochemical analyses all revealed that the LYN/HA-coated hybrid scaffolds possessed not only reliable biosafety but also excellent osteogenesis-inducing and osteoclastogenesis-inhibiting effects, resulting in faster and higher-quality bone tissue regeneration. Taken together, this study offers a powerful and promising strategy to construct multifunctional nanocomposite scaffolds by promoting osteo/angiogenesis and suppressing osteoclastogenesis to accelerate bone regeneration.

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“…Macrophage-secreting low-density lipoprotein receptor-related protein 1 or macrophage-expressed G-protein-coupled receptor-interacting protein 1 was shown to play a role in the fracture repair process in mice [ 28 , 29 ]. Qiao et al reported that the sequential activation of heterogenous macrophage phenotypes, such as M1 and M2 macrophages, was necessary for the bone regeneration process in rats [ 30 ]. These findings suggest that macrophages are key players in the bone repair process, such as the inflammatory, restoration, and remodeling phases.…”

Section: Discussionmentioning

confidence: 99%

“…M1 macrophages are related to the inflammation process in tissue repair, and alternatively activated M2 macrophages participate in tissue regeneration [ 10 , 39 ]. However, inflammatory macrophages were recently proposed to participate in the bone repair process [ 9 , 30 ]. In the present study, Dex significantly decreased the expression of M-CSF in bone tissues at the damaged site two days after bone injury in mice.…”

Section: Discussionmentioning

confidence: 99%

Role of Macrophages and Plasminogen Activator Inhibitor-1 in Delayed Bone Repair Induced by Glucocorticoids in Mice

Okada

Kawao

Nakai

et al. 2022

IJMS

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Glucocorticoids delay fracture healing and induce osteoporosis. However, the mechanisms by which glucocorticoids delay bone repair have yet to be clarified. Plasminogen activator inhibitor-1 (PAI-1) is the principal inhibitor of plasminogen activators and an adipocytokine that regulates metabolism. We herein investigated the roles of macrophages in glucocorticoid-induced delays in bone repair after femoral bone injury using PAI-1-deficient female mice intraperitoneally administered with dexamethasone (Dex). Dex significantly decreased the number of F4/80-positive macrophages at the damaged site two days after femoral bone injury. It also attenuated bone injury-induced decreases in the number of hematopoietic stem cells in bone marrow in wild-type and PAI-1-deficient mice. PAI-1 deficiency significantly weakened Dex-induced decreases in macrophage number and macrophage colony-stimulating factor (M-CSF) mRNA levels at the damaged site two days after bone injury. It also significantly ameliorated the Dex-induced inhibition of macrophage phagocytosis at the damaged site. In conclusion, we herein demonstrated that Dex decreased the number of macrophages at the damaged site during early bone repair after femoral bone injury partly through PAI-1 and M-CSF in mice.

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Sequential activation of heterogeneous macrophage phenotypes is essential for biomaterials-induced bone regeneration

Cited by 76 publications

References 78 publications

Iron Metabolism and Immune Regulation

Iron Metabolism and Immune Regulation

Mussel-inspired multifunctional surface through promoting osteogenesis and inhibiting osteoclastogenesis to facilitate bone regeneration

Role of Macrophages and Plasminogen Activator Inhibitor-1 in Delayed Bone Repair Induced by Glucocorticoids in Mice

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