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Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing.

ABSTRACT: There is an urgent clinical need for an appropriate method to shorten skin healing time. Among most factors related to wound healing, M2 macrophages will be recruited to the wound area and play a pivotal role in a time-limiting factor, angiogenesis. The exploration of exosomes derived from M2 in angiogenesis promotion is an attractive research field. In this project, we found that exosomes from M2 (M2-EXO) promoted the angiogenic ability of HUVECs in vitro. With a series of characteristic experiments, we demonstrated that M2-EXO inhibited PTEN expression in HUVECs by transferring miR-21, and further activated AKT/mTOR pathway. Then, using a full-thickness cutaneous wound mice model, we demonstrated that M2-EXO could be used as a promotor of angiogenesis and regeneration in vivo. Furthermore, M2-EXO-treated skin wounds exhibited regeneration of functional microstructures. These results demonstrate that M2-EXO can be used as a promising nanomedicine strategy for therapeutic exploration of skin healing with the potential to be translated into clinical practice.

SUBMITTER: Lyu L

PROVIDER: S-EPMC9592913 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing.

Lyu Leifeng L Cai Yuanqing Y Zhang Guangyang G Jing Zhaopu Z Liang Jialin J Zhang Rupeng R Dang Xiaoqian X Zhang Chen C

Frontiers in molecular biosciences 20221011

There is an urgent clinical need for an appropriate method to shorten skin healing time. Among most factors related to wound healing, M2 macrophages will be recruited to the wound area and play a pivotal role in a time-limiting factor, angiogenesis. The exploration of exosomes derived from M2 in angiogenesis promotion is an attractive research field. In this project, we found that exosomes from M2 (M2-EXO) promoted the angiogenic ability of HUVECs <i>in vitro</i>. With a series of characteristic ...[more]

PMID: 36304927

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Project description:The oral mucosa exhibits unique regenerative properties, sometimes referred to as foetal-like wound healing. Researchers from our institute have used sheets of oral mucosa epithelial cells (OMECs) for regenerative medicine applications including cornea replacement and oesophageal epithelial regeneration for stricture prevention. Here, we have isolated exosomes from clinical-grade production of OMEC sheets from healthy human donors (n = 8), aiming to evaluate the clinical potential of the exosomes to stimulate epithelial regeneration and to improve understanding of the mode-of-action of the cells. Exosomes were isolated from conditioned (cExo) and non-conditioned (ncExo) media. Characterization was performed using Western blot for common exosomal-markers: CD9 and flotillin were positive while annexin V, EpCam and contaminating marker GRP94 were negative. Nanoparticle tracking analysis revealed a diameter of ~120 nm and transmission electron microscopy showed a corresponding size and spherical appearance. Human skin fibroblasts exposed to exosomes showed dose-dependent reduction of proliferation and a considerable increase of growth factor gene expression (HGF, VEGFA, FGF2 and CTGF). The results were similar for both groups, but with a trend towards a larger effect from cExo. To study adhesion, fluorescently labelled exosomes were topically applied to pig oesophageal wound-beds ex vivo and subsequently washed. Positive signal could be detected after as little as 1 min of adhesion, but increased adhesion time produced a stronger signal. Next, labelled exosomes were added to full-thickness skin wounds in rats and signal was detected up to 5 days after application. cExo significantly reduced the wound size at days 6 and 17. In conclusion, exosomes from OMEC sheets showed pro-regenerative effects on skin wound healing. This is the first time that the healing capacity of the oral mucosa is studied from an exosome perspective. These findings might lead to a combinational therapy of cell sheets and exosomes for future patients with early oesophageal cancer.

Project description:Diabetic wounds are a serious complication of diabetes mellitus (DM) that can lead to persistent infection, amputation, and even death. Prolonged oxidative stress has been widely recognized as a major instigator in the development of diabetic wounds; therefore, oxidative stress is considered a promising therapeutic target. In the present study, Keap1/Nrf2 signaling was confirmed to be activated in streptozotocin (STZ)-induced diabetic mice and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). Knockdown of Keap1 by siRNA reversed the increase in Keap1 levels, promoted the nuclear translocation of Nrf2, and increased the expression of HO-1, an antioxidant protein. To explore therapeutic delivery strategies, milk-derived exosomes (mEXOs) were developed as a novel, efficient, and non-toxic siRNA carrier. SiRNA-Keap1 (siKeap1) was loaded into mEXOs by sonication, and the obtained mEXOs-siKeap1 were found to promote HUVEC proliferation and migration while relieving oxidative stress in MGO-treated HUVECs. Meanwhile, in a mouse model of diabetic wounds, injection of mEXOs-siKeap1 significantly accelerated diabetic wound healing with enhanced collagen formation and neovascularization. Taken together, these data support the development of Keap1 knockdown as a potential therapeutic strategy for diabetic wounds and demonstrated the feasibility of mEXOs as a scalable, biocompatible, and cost-effective siRNA delivery system. The therapeutic effect of siKeap1-loaded mEXOs on diabetic wound healing was assessed. First, we found that the expression of Keap1 was upregulated in the wounds of diabetic mice and in human umbilical vein endothelial cells (HUVECs) pretreated with methylglyoxal (MGO). Next, we extracted exosomes from raw milk by differential centrifugation and loaded siKeap1 into milk-derived exosomes by sonication. The in vitro application of the synthetic complex (mEXOs-siKeap1) was found to increase the nuclear localization of Nrf2 and the expression of the antioxidant protein HO-1, thus reversing oxidative stress. Furthermore, in vivo mEXOs-siKeap1 administration significantly accelerated the healing rate of diabetic wounds (Scheme 1). Scheme 1 Schematic diagram. A Synthesis of mEXOs-siKeap1 complex. B Mechanism of mEXOs-siKeap1 in vitro. C The treatment effect of mEXOs-siKeap1 on an in vivo mouse model of diabetic wounds.

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Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing.

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Exosomes derived from M2 macrophages induce angiogenesis to promote wound healing.

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