scholarly journals MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Xiaoning He ◽  
Zhiwei Dong ◽  
Yina Cao ◽  
Han Wang ◽  
Shiyu Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Wound Healing ◽  
Wound Repair ◽  
Macrophage Polarization ◽  
Therapeutic Effects ◽  
Cutaneous Wound Healing ◽  
Bone Marrow Mscs ◽  
Wound Site ◽  
Cutaneous Wound ◽  
M2 Polarization

Mesenchymal stem cell transplantation (MSCT) promotes cutaneous wound healing. Numerous studies have shown that the therapeutic effects of MSCT appear to be mediated by paracrine signaling. However, the cell-cell interaction during MSCT between MSCs and macrophages in the region of cutaneous wound healing is still unknown. In this study, early depletion of macrophages delayed the wound repair with MSC injection, which suggested that MSC-mediated wound healing required macrophages. Moreover, we demonstrated that systemically infused bone marrow MSCs (BMMSCs) and jaw bone marrow MSCs (JMMSCs) could translocate to the wound site, promote macrophages toward M2 polarization, and enhance wound healing.In vitrococulture of MSCs with macrophages enhanced their M2 polarization. Mechanistically, we found that exosomes derived from MSCs induced macrophage polarization and depletion of exosomes of MSCs reduced the M2 phenotype of macrophages. Infusing MSCs without exosomes led to lower number of M2 macrophages at the wound site along with delayed wound repair. We further showed that the miR-223, derived from exosomes of MSCs, regulated macrophage polarization by targeting pknox1. These findings provided the evidence that MSCT elicits M2 polarization of macrophages and may accelerate wound healing by transferring exosome-derived microRNA.

scholarly journals Pulmonary infection interrupts acute cutaneous wound healing through disruption of chemokine signals

2020 ◽  
Author(s):  
Meredith J. Crane ◽  
Yun Xu ◽  
Sean F. Monaghan ◽  
Benjamin M. Hall ◽  
Jorge E. Albina ◽  
...  
Keyword(s):  
Wound Healing ◽  
Immune Responses ◽  
Mouse Models ◽  
Pulmonary Infection ◽  
Lung Infection ◽  
Innate Immune ◽  
List Type ◽  
Cutaneous Wound Healing ◽  
Wound Site ◽  
Cutaneous Wound

SummaryStudies of the immune response typically focus on single-insult systems, with little known about how multi-insult encounters are managed. Pneumonia in patients recovering from surgery is a clinical situation that exemplifies the need for the patient to mount two distinct immune responses. Examining this, we have determined that poor wound healing is an unreported complication of pneumonia in laparotomy patients. Using mouse models, we found that lung infection suppressed the trafficking of innate leukocytes to wounded skin, while pulmonary resistance to the bacterial infection was maintained. The dual insults caused distinct systemic and local changes to the inflammatory response, the most striking being a rapid and sustained decrease in chemokine levels at the wound site of mice with pneumonia. Remarkably, replenishing wound chemokine levels completely rescued the wound-healing rate in mice with a pulmonary infection. These findings have broad implications for understanding the mechanisms guiding the innate immune system to prioritize inflammatory sites.One Sentence SummaryChemokine-mediated signaling drives the prioritization of innate immune responses to bacterial pulmonary infection over cutaneous wound healing.HighlightsHuman laparotomy patients with pneumonia have an increased rate of incision dehiscence, and this observation can be recapitulated in mouse models of bacterial lung infections and skin wounds.Lung infection causes rapid and sustained suppression of skin wound chemokine and inflammatory cytokine production as well as leukocyte recruitment.Unique systemic shifts in the immune compartment occur with two inflammatory insults, including the cytokine/chemokine signature and the mobilization, recruitment, and phenotype of innate leukocytes.Restoration of chemokine signaling in the wounds of mice that have a lung infection results in increased neutrophil trafficking to the wound site and rescues the rate of healing.Graphical Abstract

M2-Polarized Macrophages Mediate Wound Healing by Regulating Connective Tissue Growth Factor via AKT, ERK 1/2, and STAT 3 Signaling Pathways

2021 ◽  
Author(s):  
Si-Min Zhang ◽  
Chuan-Yuan Wei ◽  
Qiang Wang ◽  
Lu Wang ◽  
Lu Lu ◽  
...  
Keyword(s):  
Wound Healing ◽  
Tissue Growth ◽  
Cutaneous Wound Healing ◽  
M2 Macrophages ◽  
Cutaneous Wound ◽  
Stat3 Signaling ◽  
M2 Polarization ◽  
Stat3 Signaling Pathway ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Timely and sufficient recruitment of M1 macrophages and M2 polarization are necessary for fibrous repair during cutaneous wound healing. The inherent mechanism of how M2 polarization mediate wound healing is worth exploring and illustrating. Abnormally up-regulated connective tissue growth factor (CTGF) is closely related with multiple organ fibrosis, including cardiac, pulmonary, hepatic, renal, and cutaneous fibrosis. Previous studies have reported that M2-polarized macrophages contribute to hepatic and renal fibrosis by secreting CTGF. It is worth discussing if M2 macrophages regulate fibrosis through secreting CTGF in cutaneous wound healing.Methods: We established the murine full-thickness excisional wound model and inhibited macrophages during proliferation phase (mainly M2 and M1-M2 polarization) with clodronate liposomes to analyze how M2 macrophages mediate wound healing rates, collagen deposition, collagen 1/3 expression, and Ki67 expression in vivo. Furthermore, M2 polarization was induced by IL-4 and in vitro. F4/80+CD206+ M2 macrophages were measured by flow cytometry. The morphological characteristics were observed. Secretion of IL-6, TNF-α, IL-10, TGF-β1, and CTGF was tested by ELISA. CTGF gene of M2 was blocked using siCTGF. Effects of M2 on proliferation and migration of fibroblasts were detected by CCK8 and cellular wound healing assay. Protein level of AKT, ERK1/2, and STAT3 pathway were assessed by western blotting.Results: Depletion of macrophages at proliferation phase (mainly M2 and M1-M2 polarization) resulted in delayed cutaneous wound closure and down-regulation of wound healing rates, collagen deposition, collagen 1/3 expression, and Ki67 expression. M2 polarization was induced, which producing more CTGF, TGF-β1, and IL-6, as well as less TNF-α and IL-10. Blockade of CTGF in M2 macrophages deactivated fibroblast proliferation and migration. Addition of recombinant CTGF restored the promotional effects of M2 macrophages on fibroblast proliferation and migration. Blockade of CTGF in M2 mediate fibroblasts via down-regulating AKT, ERK1/2, and STAT3 signaling pathway.Conclusion: Our research, for the first time, indicated that M2-polarized macrophages promoted cutaneous wound healing by secreting CTGF, which further mediating proliferation and migration of fibroblasts via AKT, ERK1/2, and STAT3 signaling pathway.

scholarly journals RNAseq Analysis of Treatment-dependent Signaling Changes During Inflammation in a Mouse Cutaneous Wound Healing Model.

2021 ◽  
Author(s):  
III Georges St. Laurent ◽  
Ian Toma ◽  
Bernd Seilheimer ◽  
Konstantin Cesnulevicius ◽  
Myron Schultz ◽  
...  
Keyword(s):  
Wound Healing ◽  
Placebo Control ◽  
Therapeutic Effects ◽  
Mrna Levels ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound ◽  
Synthetic Pathway ◽  
Cox Inhibitor ◽  
Wound Healing Model ◽  
Healing Model

Abstract Background: Despite proven therapeutic effects in inflammatory conditions, the specific mechanisms of phytochemical therapies are not well understood. The transcriptome effects of Tr14 (Traumeel), a multicomponent natural product, and diclofenac, a non-selective cyclooxygenase (COX) inhibitor, were compared in a mouse cutaneous wound healing model to identify both known and novel pathways for the anti-inflammatory effect of plant-derived natural products. Methods: Skin samples from abraded mice were analyzed by single-molecule, amplification-free RNAseq transcript profiling at 7 points between 12-192 hours after injury. Immediately after injury, the wounds were treated with either diclofenac, Tr14, or placebo control (n=7 per group/time). RNAseq levels were compared between treatment and control at each time point using a systems biology approach. Results: At early time points (12-36 hours), both control and Tr14-treated wounds showed marked increase in the inducible COX2 enzyme mRNA, while diclofenac-treated wounds did not. Tr14, in contrast, modulated lipoxygenase transcripts, especially ALOX12/15, and phospholipases involved in arachidonate metabolism. Notably, Tr14 modulated a group of cell-type specific markers, including the T cell receptor, that could be explained by an overarching effect on the type of cells that were recruited into the wound tissue. Conclusions: Tr14 and diclofenac had very different effects on the COX/LOX synthetic pathway after cutaneous wounding. Tr14 allowed normal autoinduction of COX2 mRNA, but suppressed mRNA levels for key enzymes in the leukotriene synthetic pathway. Tr14 appeared to have a broad ‘phytocellular’ effect on the wound transcriptome by altering the balance of cell types present in the wound.

scholarly journals Human bone marrow mesenchymal stem cells-derived exosomes stimulate cutaneous wound healing mediates through TGF-β/Smad signaling pathway

2020 ◽  
Author(s):  
Tiechao Jiang ◽  
Zhongyu Wang ◽  
Ji Sun
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound ◽  
Skin Cells ◽  
Smad Signaling Pathway ◽  
Marrow Mesenchymal Stem Cells

Abstract Background: Cutaneous wound healing represents a morphogenetic response to injury, and is designed to restore anatomic and physiological function. Human bone marrow mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) is a promising source for cell-free therapy and skin regeneration. Methods: In this study, we investigated the cell regeneration effects and its underlying mechanism of hBM-MSCs-Ex on cutaneous wound healing in rats. In vitro studies, we evaluated the role of hBM-MSCs-Ex in the two types of skin cells: human keratinocytes (HaCaT) and human dermal fibroblasts (HDFs) for the proliferation. For in vivo studies, we used a full-thickness skin wound model to evaluate the effects of hBM-MSCs-Ex on cutaneous wound healing in vivo. Results: The results demonstrated that hBM-MSCs-Ex promote both two types of skin cells growth effectively and accelerate the cutaneous wound healing. Interestingly, we found that hBM-MSCs-Ex significantly down-regulated TGF-β1, Smad2, Smad3, and Smad4 expression, while up-regulated TGF-β3 and Smad7 expression in the TGF-β/Smad signaling pathway. Conclusions: Our findings indicated that hBM-MSCs-Ex effectively promote the cutaneous wound healing through inhibiting the TGF-β/Smad signal pathway. The current results providing a new sight for the therapeutic strategy for the treatment of cutaneous wounds.

scholarly journals Human bone marrow mesenchymal stem cells-derived exosomes stimulate cutaneous wound healing mediates through TGF-β/Smad signaling pathway

2020 ◽  
Author(s):  
Tiechao Jiang ◽  
Zhongyu Wang ◽  
Ji Sun
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Cutaneous Wound Healing ◽  
Cutaneous Wound ◽  
Skin Cell ◽  
Smad Signaling Pathway ◽  
Marrow Mesenchymal Stem Cells

Abstract Background: Cutaneous wound healing represents a morphogenetic response to injury, and is designed to restore anatomic and physiological function. Human bone marrow mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) is a promising source for cell-free therapy and skin regeneration. Methods: In this study, we investigated the cell regeneration effects and its underlying mechanism of hBM-MSCs-Ex on cutaneous wound healing in rats. In vitro studies , w e evaluated the role of hBM-MSCs-Ex in the two type s of skin cell s : human keratinocytes (HaCaT) and human dermal fibroblasts (HDFs) for the proliferation . For in vivo studies , we used a full-thickness skin wound model to evaluate the effects of hBM-MSCs-Ex on cutaneous wound healing in vivo . Results: The results demonstrated that hBM-MSCs-Ex promote both two type s of skin cell s growth effectively and accelerate the cutaneous wound healing. Interestingly , we found that hBM-MSCs-Ex significantly down-regulated TGF-β1, Smad2, Smad3, and Smad4 expression, while up-regulated TGF-β3 and Smad7 expression in the TGF-β/Smad signaling pathway . Conclusions: Our findings indicated that hBM-MSCs-Ex effectively promote the cutaneous wound healing through inhibiting the TGF-β/Smad signal pathway . The current result s providing a new sight for the therapeutic strategy for the treatment of cutaneous wounds.

scholarly journals Apoptotic bodies derived from mesenchymal stem cells promote cutaneous wound healing via regulating the functions of macrophages

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jin Liu ◽  
Xinyu Qiu ◽  
Yajie Lv ◽  
Chenxi Zheng ◽  
Yan Dong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Mesenchymal Stem Cells ◽  
Mouse Skin ◽  
Skin Wound ◽  
Therapeutic Effects ◽  
Cutaneous Wound Healing ◽  
Apoptotic Bodies ◽  
Skin Wound Healing ◽  
Cutaneous Wound

Abstract Background As the major interface between the body and the external environment, the skin is liable to various injuries. Skin injuries often lead to severe disability, and the exploration of promising therapeutic strategies is of great importance. Exogenous mesenchymal stem cell (MSC)-based therapy is a potential strategy due to the apparent therapeutic effects, while the underlying mechanism is still elusive. Interestingly, we observed the extensive apoptosis of exogenous bone marrow mesenchymal stem cells (BMMSCs) in a short time after transplantation in mouse skin wound healing models. Considering the roles of extracellular vesicles (EVs) in intercellular communication, we hypothesized that the numerous apoptotic bodies (ABs) released during apoptosis may partially contribute to the therapeutic effects. Methods ABs derived from MSCs were extracted, characterized, and applied in mouse skin wound healing models, and the therapeutic effects were evaluated. Then, the target cells of ABs were explored, and the effects of ABs on macrophages were investigated in vitro. Results We found ABs derived from MSCs promoted cutaneous wound healing via triggering the polarization of macrophages towards M2 phenotype. In addition, the functional converted macrophages further enhanced the migration and proliferation abilities of fibroblasts, which together facilitated the wound healing process. Conclusions Collectively, our study demonstrated that transplanted MSCs promoted cutaneous wound healing partially through releasing apoptotic bodies which could convert the macrophages towards an anti-inflammatory phenotype that plays a crucial role in the tissue repair process.

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