Dataset Information

Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing.

ABSTRACT: Macrophages (M?s) critically contribute to wound healing by coordinating inflammatory, proliferative, and angiogenic processes. A proper switch from proinflammatory M1 to anti-inflammatory M2 dominant M?s accelerates the wound healing processes leading to favorable wound-care outcomes. Herein, an exosome-guided cell reprogramming technique is proposed to directly convert M1 to M2 M?s for effective wound management. The M2 M?-derived exosomes (M2-Exo) induce a complete conversion of M1 to M2 M?s in vitro. The reprogrammed M2 M?s turn Arginase (M2-marker) and iNOS (M1-marker) on and off, respectively, and exhibit distinct phenotypic and functional features of M2 M?s. M2-Exo has not only M? reprogramming factors but also various cytokines and growth factors promoting wound repair. After subcutaneous administration of M2-Exo into the wound edge, the local populations of M1 and M2 M?s are markedly decreased and increased, respectively, showing a successful exosome-guided switch to M2 M? polarization. The direct conversion of M1 to M2 M?s at the wound site accelerates wound healing by enhancing angiogenesis, re-epithelialization, and collagen deposition. The M? phenotype switching induced by exosomes possessing the excellent cell reprogramming capability and innate biocompatibility can be a promising therapeutic approach for various inflammation-associated disorders by regulating the balance between pro- versus anti-inflammatory M?s.

SUBMITTER: Kim H

PROVIDER: S-EPMC6794619 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing.

Kim Hyosuk H Wang Sun Young SY Kwak Gijung G Yang Yoosoo Y Kwon Ick Chan IC Kim Sun Hwa SH

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190827 20

Macrophages (Mϕs) critically contribute to wound healing by coordinating inflammatory, proliferative, and angiogenic processes. A proper switch from proinflammatory M1 to anti-inflammatory M2 dominant Mϕs accelerates the wound healing processes leading to favorable wound-care outcomes. Herein, an exosome-guided cell reprogramming technique is proposed to directly convert M1 to M2 Mϕs for effective wound management. The M2 Mϕ-derived exosomes (M2-Exo) induce a complete conversion of M1 to M2 Mϕs ...[more]

PMID: 31637157

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Project description:Bidirectional cell-cell communication involving exosome-borne cargo such as miRNA has emerged as a critical mechanism for wound healing. Unlike other shedding vesicles, exosomes selectively package miRNA by SUMOylation of heterogeneous nuclear ribonucleoproteinA2B1 (hnRNPA2B1). In this work, we elucidate the significance of exosome in keratinocyte-macrophage crosstalk following injury. Keratinocyte-derived exosomes were genetically labeled with GFP-reporter (Exoκ-GFP) using tissue nanotransfection (TNT), and they were isolated from dorsal murine skin and wound-edge tissue by affinity selection using magnetic beads. Surface N-glycans of Exoκ-GFP were also characterized. Unlike skin exosome, wound-edge Exoκ-GFP demonstrated characteristic N-glycan ions with abundance of low-base-pair RNA and was selectively engulfed by wound macrophages (ωmϕ) in granulation tissue. In vitro addition of wound-edge Exoκ-GFP to proinflammatory ωmϕ resulted in conversion to a proresolution phenotype. To selectively inhibit miRNA packaging within Exoκ-GFP in vivo, pH-responsive keratinocyte-targeted siRNA-hnRNPA2B1 functionalized lipid nanoparticles (TLNPκ) were designed with 94.3% encapsulation efficiency. Application of TLNPκ/si-hnRNPA2B1 to the murine dorsal wound-edge significantly inhibited expression of hnRNPA2B1 by 80% in epidermis compared to the TLNPκ/si-control group. Although no significant difference in wound closure or re-epithelialization was observed, the TLNPκ/si-hnRNPA2B1 treated group showed a significant increase in ωmϕ displaying proinflammatory markers in the granulation tissue at day 10 post-wounding compared to the TLNPκ/si-control group. Furthermore, TLNPκ/si-hnRNPA2B1 treated mice showed impaired barrier function with diminished expression of epithelial junctional proteins, lending credence to the notion that unresolved inflammation results in leaky skin. This work provides insight wherein Exoκ-GFP is recognized as a major contributor that regulates macrophage trafficking and epithelial barrier properties postinjury.

Project description:BackgroundThe anti-inflammatory properties of the cannabinoid 2 receptor (CB2R) in injury and inflammatory diseases have been widely substantiated. Specifically, the anti-inflammatory effect of CB2R may be achieved by regulating macrophage polarisation. Several research findings suggested that the activation of CB2R could attenuate inflammation by reducing pro-inflammatory M1 macrophage polarisation and promoting anti-inflammatory M2 polarisation. However, considering CB2R inhibits fibrosis and M2 promotes fibrosis, that the activation of CB2R may lead to an increase in M2 macrophages seems contradictory. Therefore, we hypothesised that the activation of CB2R to attenuate inflammation is not achieved by up-regulating M2 macrophages.MethodsWe established an incised wound model using mouse skin and used this to evaluate the effect of CB2R agonists (JWH133 or GP1a) and an antagonist (AM630) on wound healing. At various post-injury intervals, we used western blot analysis, immunofluorescence staining, enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction assays to determine CB2R protein expression, M1/M2 macrophage infiltration, and the protein and gene expression of M1/M2-associated markers and cytokines in skin lesions.ResultsActivation of CB2R significantly reduced M1 macrophage infiltration and slightly increased M2 macrophage infiltration. Similarly, gene expression and protein levels of M1-associated markers and cytokines (interleukin [IL]-6, IL-12, CD86 and inducible nitric oxide synthase) were significantly down-regulated after CB2R agonist administration; in contrast, markers and cytokines were increased in the CB2R antagonist-treated group. Conversely, the administration of agonists slightly increased gene expression and protein levels of M2-associated markers and cytokines (IL-4, IL-10, CD206 and arginase-1 [Arg-1]); however, a statistical significance at most time points post-injury was not noted.ConclusionIn summary, our findings suggested that during incised skin wound healing in mice, increased levels of CB2R may affect inflammation by regulating M1 rather than M2 macrophage subtype polarisation. These results offer a novel understanding of the molecular mechanisms involved in the inhibition of inflammation by CBR2 that may lead to new treatments for cutaneous inflammation.

Dataset Information

Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing.

Publications

Exosome-Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing.

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