Macrophages as a therapeutic target to promote diabetic wound healing

Sharifiaghdam, Maryam; Shaabani, Elnaz; Faridi‐Majidi, Reza; Smedt, Stefaan C. De; Braeckmans, Kevin; Fraire, Juan C.

doi:10.1016/j.ymthe.2022.07.016

Cited by 115 publications

(47 citation statements)

References 163 publications

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“…Macrophages are the key to timely wound healing. 48 Our study found that the removal of macrophages from mice resulted in significantly slower wound healing, poorer tissue healing and a significant reduction in collagen. The IHC further confirms these observations.…”

Section: Discussionmentioning

confidence: 56%

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Kuang¹,

Zhang²,

Li³

et al. 2023

IJN

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Purpose Diabetic wound is a highly prevalent and refractory disease. Extensive studies have confirmed that keratinocytes and macrophages play an important role in the process of wound healing. Additionally, exosomes are regarded as a vital intercellular communication tool. This study aimed to investigate the role of human keratinocyte-derived exosomal MALAT1 in the treatment of diabetic wound by influencing the biological function of macrophages. Methods We mainly assessed the function of MALAT1 on the biological changes of macrophages, and the expression of MALAT1 in the keratinocyte-exosomes analyzed by quantitative real-time polymerase chain reaction (RT-qPCR). The downstream interaction between RNAs or proteins was assessed by mechanistic experiments. Besides, we evaluated the effects of human keratinocyte-derived exosomal MALAT1 on diabetic wound healing in vivo to verify in vitro results. Results We demonstrated that human keratinocyte-derived exosomal MALAT1 enhanced the biological functions of high glucose-injured macrophages, including phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. Mechanistically, MALAT1 accelerated the expression of MFGE8 by competitively binding to miR-1914-3p, thereby affecting the function of macrophages and the signal axis of TGFB1/SMAD3, and finally promoting the healing of diabetic wounds. Human keratinocyte-derived exosomal MALAT1 might promote collagen deposition, ECM remodeling, and expression of MFGE8, VEGF, and CD31 but reduce the expression of TGFB and SMAD3 in an in vivo model of diabetic mice wounds, which accelerated diabetic wound healing and restored its function. Conclusion The current study revealed that human keratinocyte-derived exosomal MALAT1 would suppress miR-1914-3p to activate MFGE8 and eventually promote wound healing by enhancing macrophage phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. It proposed that keratinocyte-derived exosomes might have the capacity to serve as a new method for the clinical treatment of diabetic wound.

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Section: Discussionmentioning

confidence: 56%

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Kuang¹,

Zhang²,

Li³

et al. 2023

IJN

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“…Given that a deficiency in M2 reparative macrophages contributes to chronic inflammation and impaired wound healing, including in diabetic wound, , interventions that promote M2 polarization of macrophages may improve wound healing. , With a decrease in macrophage infiltration to the wound at early phase following treatment with dasatinib ointments, our data showed that the numbers of CD206 + cells were comparable to untreated mice, suggesting that the majority of wound macrophages in dasatinib-treated groups, particularly 0.1% dasatinib, might be M2 populations. The prohealing phenotype of M2 macrophages ,, might also support the reduced inflammation and enhanced angiogenesis during dasatinib treatment.…”

Section: Discussionmentioning

confidence: 60%

“…33,46 With a decrease in macrophage infiltration to the wound at early phase following treatment with dasatinib ointments, our data showed that the numbers of CD206 + cells were comparable to untreated mice, suggesting that the majority of wound macrophages in dasatinib-treated groups, particularly 0.1% dasatinib, might be M2 populations. The prohealing phenotype of M2 macrophages 34,45,47 might also support the reduced inflammation and enhanced angiogenesis during dasatinib treatment. In agreement with our observations, a previous study has reported that macrophage depletion did not affect the early phase of wound healing, but led to defective angiogenesis and delayed healing in the later phase due to a lack of M2 macrophages.…”

Section: ■ Discussionmentioning

confidence: 93%

“…44 More importantly, 0.02−0.1% topical dasatinib solutions, comparable concentrations to our study, have been shown to attenuate inflammation in an animal model of atopic dermatitis, 24 supporting the potential anti-inflammatory activity of dasatinib ointment. Given that a deficiency in M2 reparative macrophages contributes to chronic inflammation and impaired wound healing, including in diabetic wound, 33,45 interventions that promote M2 polarization of macrophages may improve wound healing. 33,46 With a decrease in macrophage infiltration to the wound at early phase following treatment with dasatinib ointments, our data showed that the numbers of CD206 + cells were comparable to untreated mice, suggesting that the majority of wound macrophages in dasatinib-treated groups, particularly 0.1% dasatinib, might be M2 populations.…”

Section: ■ Discussionmentioning

confidence: 99%

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Dasatinib Ointment Promotes Healing of Murine Excisional Skin Wound

Wichaiyo

Svasti

Maiuthed

et al. 2023

ACS Pharmacol. Transl. Sci.

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Dasatinib, a tyrosine kinase inhibitor, has been shown to produce anti-inflammatory activity and impair vascular integrity in vivo, including during skin wound healing, potentially promoting the repair process. Given that dasatinib is a lipophilic small molecule capable of penetrating skin, topical dasatinib might provide benefits in wound healing. In the present study, we investigated the impact of dasatinib ointments in skin wound healing in mice. A full thickness excisional skin wound (4 mm diameter) was generated on the shaved dorsum of eightweek-old C57BL/6 mice. Dasatinib ointment (0.1 or 0.2% w/w) or ointment base was applied twice daily (every 12 h) for 10 days. Elizabethan collars were used to prevent animal licking. The wound size was monitored daily for 14 days. The results showed that dasatinib ointments, particularly 0.1% dasatinib, promoted a 16−23% reduction in wound size (p < 0.05) during day 2 to day 6 postinjury compared to controls. Immunohistochemistry analyses demonstrated a reduction in wound neutrophils (38% reduction, p = 0.04), macrophages (47% reduction, p = 0.005), and tumor necrosis factor-α levels (73% reduction, p < 0.01), together with an induction of vascular leakage-mediated fibrin(ogen) accumulation (2.5-fold increase, p < 0.01) in the wound during day 3 postinjury (an early phase of repair) in 0.1% dasatinib-treated mice relative to control mice. The anti-inflammatory and vascular hyperpermeability activities of dasatinib were associated with an enhanced healing process, including increased keratinocyte proliferation (1.8-fold increase in Ki67 + cells, p < 0.05) and augmented angiogenesis (1.7-fold increase in CD31 + area, p < 0.05), compared to the ointment base-treated group. Following treatment with 0.2% dasatinib ointment, minor wound bleeding and scab reformation were observed during the late phase, which contributed to delayed healing. In conclusion, our data suggest that dasatinib ointment, mainly at 0.1%, promotes the repair process by reducing inflammation and producing a local and temporal vascular leakage, leading to an increase in fibrin(ogen) deposition, re-epithelialization, and angiogenesis. Therefore, topical dasatinib might be a potential novel candidate to facilitate skin wound healing.

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“…M1 polarization of macrophages is a major cause for excessive inflammation during diabetic wound healing [ 18 ]. The TNF-α level is increased in diabetic wounds, provoking macrophage M1 polarization [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Local Application of Krill Oil Accelerates the Healing of Artificially Created Wounds in Diabetic Mice

Hao

Meng

et al. 2022

Nutrients

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Diabetes mellitus (DM) impairs the wound healing process, seriously threatening the health of the diabetic population. To date, few effective approaches have been developed for the treatment of diabetic wounds. Krill oil (KO) contains bioactive components that have potent anti-inflammatory and anti-oxidative activities. As prolonged inflammation is a crucial contributor to DM-impaired wound healing, we speculated that the local application of KO would accelerate diabetic wound healing. Therefore, KO was applied to artificially created wounds of type 2 diabetic mice induced by streptozotocin and high-fat diet. The diabetic mice had a delayed wound healing process compared with the non-diabetic control mice, with excessive inflammation, impaired collagen deposition, and depressed neovascularization in the wound area. These effects were dramatically reversed by KO. In vitro, KO blocked the TNF-α-induced macrophage inflammation, fibroblast dysfunction, and endothelial angiogenic impairment. The present study in mice suggests that KO local application could be a viable approach in the management of diabetic wounds.

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Macrophages as a therapeutic target to promote diabetic wound healing

Cited by 115 publications

References 163 publications

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Dasatinib Ointment Promotes Healing of Murine Excisional Skin Wound

Local Application of Krill Oil Accelerates the Healing of Artificially Created Wounds in Diabetic Mice

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