The Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles (MSC-EVs) in Promoting M2 Macrophage Polarization in Severe Cutaneous Burn Wounds Following MSC Treatment
Ian T. Bui
Introduction. Severe cutaneous burn wound is classified as a third- or higher-degree full thickness burn that involves destruction of epidermis and dermis1. Macrophages influence all steps in wound healing through their phenotypic polarization: pro-inflammatory M1 phenotype and anti-inflammatory M2 phenotype2,3. Traditional treatments such as Early Excision and Grafting (EE&G) have many limitations, indicating a need for novel burn wound therapy1. A recent study reported that injecting mesenchymal stem cells (MSCs) in burn wound lowered contracture and hypertrophic scars in patients compared to EE&G4. Also, MSC-derived extracellular vesicles (MSC-EVs) promoted M2 phenotype and suppressed M1 polarization5. These findings support the potential use of MSC-EVs for the treatment of full thickness wounds. Methods. C57BL/6J and BALB/c mice were used to create full-thickness wounds and human monocytes, human jawbone marrow-derived MSC (JMMSCs) or human bone marrow-derived MSCs (BMMSCs) were injected in wound sites. To determine the M2 polarization upon MSC or MSC-EV treatment, the expression of M2 markers (RELM-α, CD206, Arginase-1, Fizz-1 and CD 206) in wound sites were examined with immunohistochemistry, western blot, and RT-PCR assays6,7. As a control, SiRab27a was transfected in MSCs to inhibit EV release6. There is no method for in vitro studies with miRNA-223 and TGF-b1. Results. Macrophage-depletion MSCs and saline groups exhibited slower wound closure after 12-day assessment compared to macrophage presence MSCs groups. Systematically infused MSCs homed to wound sites, and M2 polarization occurred at wound site, not at normal skin. Also, MSC treatments showed more effectiveness in cutaneous wound healing in mice than siRab27a transfected MSC treatment. In vitro studies showed that EVs carrying miR-223 induced M2 macrophage polarization by targeting Pknox1. Conversely, inhibiting miR-223 in EVs reduced the M2 macrophage polarization6. There are no results of Wang et al paper (TGF-β1, carried by MSC-EVs, promoted M2 phenotype and suppressed M1 polarization via MiR-132/Mycbp2/TSC2 pathway)7. Conclusions. MSCs were found to promote wound healing via immunomodulating effects through secreting EVs. Mechanistically, MSC-EVs induced anti-inflammatory M2 phenotype while suppressing pro-inflammatory M1 phenotype and miR-223 and TGF-b1 are key molecules responsible for the EV-mediated M2 polarization.
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