Macrophage Control of Incipient Bone Formation in Diabetic Mice

Kang, Miya; Thalji, Ghadeer; Huang, Chun Chieh; Shirazi, Sajjad; Lu, Yu; Ravindran, Sriram; Cooper, Lyndon F.

doi:10.3389/fcell.2020.596622

Cited by 11 publications

(14 citation statements)

References 54 publications

(63 reference statements)

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“…Published studies have shown the relationship between inflammation and bone regeneration and the effects of the secretome of macrophages on MSC differentiation and osteoinduction ( 27 , 28 ). One of the factors secreted by macrophages that positively influences bone repair is oncostatin M (OSM) ( 29 ).…”

Section: Resultsmentioning

confidence: 99%

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Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

et al. 2022

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Mesenchymal stem cells show remarkable versatility and respond to extracellular and micro environmental cues by altering their phenotype and behavior. In this regard, the MSC’s immunomodulatory properties in tissue repair are well documented. The paracrine effects of MSCs in immunomodulation are, in part, attributable to their secreted extracellular vesicles (EVs). When MSCs migrate to the wound bed, they are exposed to a myriad of inflammatory signals. To understand their response to an inflammatory environment from an EV perspective, we sought to evaluate the effects of the inflammatory cytokine TNFα on MSC EV mediated immunomodulation. Our results indicate that while the physical characteristics of the EVs remain unchanged, the TNFα preconditioned MSC EVs possess enhanced immunomodulatory properties. In vitro experiments using polarized (M1 and M2) primary mouse macrophages indicated that the preconditioned MSC EVs suppressed pro-inflammatory (M1) markers such as IL-1β and iNOS and elevated reparatory (M2) markers such as Arg1 and CD206. When evaluated in vivo in a rat calvarial defect model, the TNFα preconditioned MSC EVs reduced inflammation at 1-, 3- and 7-days post wounding resulting in the subsequent enhanced bone formation at 4- and 8-weeks post wounding possibly by modulation of oncostatin M (OSM) expression. An analysis of EV miRNA composition revealed significant changes to anti-inflammatory miRNAs in the preconditioned MSC EVs hinting at a possible role for EV derived miRNA in the enhanced immunomodulatory activity. Overall, these results indicate that MSC exposure to inflammatory signals influence the MSC EV’s immunomodulatory function in the context of tissue repair. The specific function of TNFα preconditioned MSC EV miRNAs in immunomodulatory control of bone regeneration merits further investigation.

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Section: Resultsmentioning

confidence: 99%

“…Mouse bone marrow derived macrophages (BMMs) were isolated from 8-week-old C57BL/6J mice as per previously published protocol ( 27 ). BMMs were cultured in Dulbecco’s Modified Eagle Medium (DMEM, Gibco) containing 20% fetal bovine serum (Gibco) and 1% antibiotic-antimycotic solution (Gibco).…”

Section: Methodsmentioning

confidence: 99%

Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

et al. 2022

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“…Exosomes could be used as biomimetic tools to induce migration, proliferation, and odontoblast-specific differentiation of stem cells in regenerative therapy. Based on this evidence, it is possible to speculate that dentin-based particles may have a positive effect on the differentiation of naïve cells, inducing them to produce exosomes that directly trigger odontoblastogenetic regeneration [ 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

Dentin Particulate for Bone Regeneration: An In Vitro Study

Brunello

Zanotti

Scortecci³

et al. 2022

IJMS

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The aim of this in vitro study was to investigate the commitment and behavior of dental pulp stem cells (DPSCs) seeded onto two different grafting materials, human dentin particulate (DP) and deproteinized bovine bone matrix (BG), with those cultured in the absence of supplements. Gene expression analyses along with epigenetic and morphological tests were carried out to examine odontogenic and osteogenic differentiation and cell proliferation. Compressive testing of the grafting materials seeded with DPSCs was performed as well. DPSC differentiation into odontoblast-like cells was identified from the upregulation of odontogenic markers (DSPP and MSX) and osteogenic markers (RUNX2, alkaline phosphatase, osteonectin, osteocalcin, collagen type I, bmp2, smad5/8). Epigenetic tests confirmed the presence of miRNAs involved in odontogenic or osteogenic commitment of DPSCs cultured for up to 21 days on DP. Compressive strength values obtained from extracellular matrix (ECM) synthesized by DPSCs showed a trend of being higher when seeded onto DP than onto BG. High expression of VEGF factor, which is related to angiogenesis, and of dentin sialoprotein was observed only in the presence of DP. Morphological analyses confirmed the typical phenotype of adult odontoblasts. In conclusion, the odontogenic and osteogenic commitment of DPSCs and their respective functions can be achieved on DP, which enables exceptional dentin and bone regeneration.

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“…Human bone marrow derived stromal cells (HMSCs) were obtained from Lonza and cultured in αMEM basal media (Gibco) supplemented with 20% fetal bovine serum (FBS, Gibco), 1% l -glutamate (Gibco) and 1% antibiotic, antimycotic solution (Gibco) ( Huang et al, 2020b ). Primary bone marrow derived monocytes were isolated from mouse marrow as per our previously published protocols ( Kang et al, 2020a ; Kang et al, 2020b ; Kang et al, 2022 ). The monocytes were differentiated into macrophages using macrophage colony stimulating factor (M-CSF) and subsequently polarized into pro-inflammatory (M1) or pro-reparative (M2) macrophages using LPS/IFNγ and IL-4 respectively as per previously published methodology ( Kang et al, 2020a ; Kang et al, 2020b ; Kang et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

“…Primary bone marrow derived monocytes were isolated from mouse marrow as per our previously published protocols ( Kang et al, 2020a ; Kang et al, 2020b ; Kang et al, 2022 ). The monocytes were differentiated into macrophages using macrophage colony stimulating factor (M-CSF) and subsequently polarized into pro-inflammatory (M1) or pro-reparative (M2) macrophages using LPS/IFNγ and IL-4 respectively as per previously published methodology ( Kang et al, 2020a ; Kang et al, 2020b ; Kang et al, 2022 ).…”

Section: Methodsmentioning

confidence: 99%

Micro RNA based MSC EV engineering: Targeting the BMP2 cascade for bone repair

Huang

Kang²,

Leung³

et al. 2023

Front. Cell Dev. Biol.

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Mesenchymal stem cell derived extracellular vesicles (MSC EVs) possess excellent immunomodulatory and therapeutic properties. While beneficial, from a translational perspective, extracellular vesicles with consistent functionality and target specificity are required to achieve the goals of precision medicine and tissue engineering. Prior research has identified that the miRNA composition of mesenchymal stem cell derived extracellular vesicles contributes significantly towards extracellular vesicles functionality. In this study, we hypothesized that mesenchymal stem cell derived extracellular vesicle functionality can be rendered pathway-specific using a miRNA-based extracellular vesicles engineering approach. To test this hypothesis, we utilized bone repair as a model system and the BMP2 signaling cascade as the targeted pathway. We engineered mesenchymal stem cell extracellular vesicles to possess increased levels of miR-424, a potentiator of the BMP2 signaling cascade. We evaluated the physical and functional characteristics of these extracellular vesicles and their enhanced ability to trigger the osteogenic differentiation of naïve mesenchymal stem cell in vitro and facilitate bone repair in vivo. Results indicated that the engineered extracellular vesicles retained their extracellular vesicles characteristics and endocytic functionality and demonstrated enhanced osteoinductive function by activating SMAD1/5/8 phosphorylation and mesenchymal stem cell differentiation in vitro and enhanced bone repair in vivo. Furthermore, the inherent immunomodulatory properties of the mesenchymal stem cell derived extracellular vesicles remained unaltered. These results serve as a proof-of-concept for miRNA-based extracellular vesicles engineering approaches for regenerative medicine applications.

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Macrophage Control of Incipient Bone Formation in Diabetic Mice

Cited by 11 publications

References 54 publications

Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

Extracellular Vesicles From TNFα Preconditioned MSCs: Effects on Immunomodulation and Bone Regeneration

Dentin Particulate for Bone Regeneration: An In Vitro Study

Micro RNA based MSC EV engineering: Targeting the BMP2 cascade for bone repair

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