CCL2-Mediated Reversal of Impaired Skin Wound Healing in Diabetic Mice by Normalization of Neovascularization and Collagen Accumulation

Ishida, Yuko; Kuninaka, Yumi; Nosaka, Mizuho; Furuta, Machi; Kimura, Akihiko; Taruya, Akira; Yamamoto, Hiroki; Shimada, Emi; Akiyama, Mitoshi; Mukaida, Naofumi; Kondo, Toshikazu

doi:10.1016/j.jid.2019.05.022

Cited by 61 publications

(58 citation statements)

References 51 publications

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“…CCL2, a chemokine identified in MSC extracellular vesicles, 51 recruits monocytes, memory T cells, and dendritic cells 52,53 . A recent study has shown that CCL2 concentration is decreased in diabetic wounds and topical application of CCL2 improved the delayed healing in diabetic mice 54 . Here, we observed a similar effect, in that when the diabetic wounds healed with the MSC/T/H/S device treatment, the CCL2 expression level in the wound tissue was also significantly elevated compared to the control treatment (Figure 3A).…”

Section: Resultsmentioning

confidence: 99%

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice

Yang

Fierro

et al. 2020

Stem Cells Translational Medicine

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Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)-based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia-preconditioned, allogeneic human MSCs combined with the beta-adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 μM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 10 5 cells/cm 2 on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7-day treatment, accumulative steady-state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the proinflammatory cytokines IL-1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an antiinflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5-fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the Hsin-ya Yang and Fernando Fierro contributed equally to this study.

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Section: Resultsmentioning

confidence: 99%

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice

Yang

Fierro

et al. 2020

Stem Cells Translational Medicine

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“…[88][89][90] Despite MCP-1 being generally described as a pro-inflammatory marker, several studies have also reported it to have a robust role in wound healing. [91][92][93] In contrast, RANTES, unlike MCP-1, is generally considered deleterious to the alternative noninflammatory roles of macrophages. 94,95 Therefore, its suppression appears to be desirable toward altering inflammatory polarization states.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol-Driven Alterations to Inflammatory Protein Landscape of Lipopolysaccharide-Activated Macrophages In Vitro May Be Mediated by Autophagy and Oxidative Stress

Yeisley

Arabiyat

Hahn

2021

Cannabis and Cannabinoid Research

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Background: The nonpsychotropic phytocannabinoid cannabidiol (CBD) presents itself as a potentially safe and effective anti-inflammatory treatment relative to clinical standards. In this present study, we compare the capacity of CBD to the corticosteroid dexamethasone (Dex) in altering the secreted protein landscape of activated macrophages and speculate upon the mechanism underpinning these alterations. Materials and Methods: Human THP-1 monocytes were differentiated into macrophages (THP-1 derived macrophages [tMACs]), activated with lipopolysaccharide (LPS), and then treated with 5, 10, 25, 50, or 100 lM CBD or 10 lM Dex for 24 h. Following treatment, cytotoxicity of CBD and protein expression levels from culture supernatants and from whole cell lysates were assessed for secreted and intracellular proteins, respectively. Results: High concentration (50 and 100 lM) CBD treatments exhibit a cytotoxic effect on LPS-activated tMACs following the 24-h treatment. Relative to the LPS-activated and untreated control (M[LPS]), both 25 lM CBD and 10 lM Dex reduced expression of pro-inflammatory markers-tumor necrosis factor alpha, interleukin 1 beta, and regulated on activation, normal T cell expressed and secreted (RANTES)-as well as the pleiotropic marker interleukin-6 (IL-6). A similar trend was observed for anti-inflammatory markers interleukin-10 and vascular endothelial growth factor (VEGF). Dex further reduced secreted levels of monocyte chemoattractant protein-1 in addition to suppressing IL-6 and VEGF beyond treatments with CBD. The anti-inflammatory capacity of 25 lM CBD was concurrent with reduction in levels of phosphorylated mammalian target of rapamycin Ser 2448, endothelial nitric oxide synthase, and induction of cyclooxygenase 2 relative to M(LPS). This could suggest that the observed effects on macrophage immune profile may be conferred through inhibition of mammalian target of rapamycin complex 1 and ensuing induction of autophagy. Conclusion: Cumulatively, these data demonstrate cytotoxicity of high concentration CBD treatment. The data reported herein largely agree with other literature demonstrating the anti-inflammatory effects of CBD. However, there is discrepancy within literature surrounding efficacious concentrations and effects of CBD on specific secreted proteins. These data expand upon previous work investigating the effects of CBD on inflammatory protein expression in macrophages, as well as provide insight into the mechanism by which these effects are conferred.

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“…Macrophages are key in wound repair and can be central in the process by promoting a resolution of inflammation leading to tissue repair. CCL2, the major macrophage chemoattractant, can reverse the impaired wound healing in diabetic mice (101) and HBD3 can chemoattract macrophages through CCR2 and also modulate pattern recognition receptors relevant to wound repair (102,103). As with all resolution milieu, successful wound healing will be multifactorial, but these data suggest that β-defensins are likely to contribute.…”

Section: Wound Healing Resolutionmentioning

confidence: 99%

The Dichotomous Responses Driven by β-Defensins

2020

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Defensins are short, rapidly evolving, cationic antimicrobial host defence peptides with a repertoire of functions, still incompletely realised, that extends beyond direct microbial killing. They are released or secreted at epithelial surfaces, and in some cases, from immune cells in response to infection and inflammation. Defensins have been described as endogenous alarmins, alerting the body to danger and responding to inflammatory signals by promoting both local innate and adaptive systemic immune responses. However, there is now increasing evidence that they exert variable control on the response to danger; creating a dichotomous response that can suppress inflammation in some circumstances but exacerbate the response to danger and damage in others and, at higher levels, lead to a cytotoxic effect. Focussing in this review on human β-defensins, we discuss the evidence for their functions as proinflammatory, immune activators amplifying the response to infection or damage signals and/or as mediators of resolution of damage, contributing to a return to homeostasis. Finally, we consider their involvement in the development of autoimmune diseases.

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CCL2-Mediated Reversal of Impaired Skin Wound Healing in Diabetic Mice by Normalization of Neovascularization and Collagen Accumulation

Cited by 61 publications

References 51 publications

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice

Combination product of dermal matrix, human mesenchymal stem cells, and timolol promotes diabetic wound healing in mice

Cannabidiol-Driven Alterations to Inflammatory Protein Landscape of Lipopolysaccharide-Activated Macrophages In Vitro May Be Mediated by Autophagy and Oxidative Stress

The Dichotomous Responses Driven by β-Defensins

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