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 phenotype^2,3. Traditional treatments such as Early Excision and Grafting (EE&G) have many limitations indicating a need for novel burn wound therapy¹. Many studies indicated beneficial roles of mesenchymal stem cell (MSC), a multipotent stem cell, in treating full thickness wounds through secreting MSC-derived extracellular vesicles (MSC-EVs). For example, Abo-Elkheir et al. demonstrated that injecting MSCs in burn wound lowered contracture and hypertrophic scars in patients compared to EE&G; Wang et al. showed TGF-β1, carried by MSC-EVs to macrophage, promoted M2 phenotype and suppressed M1 polarization via MiR-132/Mycbp2/TSC2 pathway^4,5. Methods. He et al. utilized C57BL/6J mice to create full-thickness wounds. Human monocytes, exosomes Human jawbone marrow-derived MSC (JMMSCs), and human bone marrow-derived MSCs (BMMSCs) were injected in wound sites. Immunohistochemistry markers include CD68+ (macrophages), RELM-α (M2), and CD206 (M2). SiRab27a was used to inhibit exosomes release⁶. Gou et al. utilized BALB/c mice. Arginase-1, Fizz-1 and CD 206 were used as M2 markers. RT-PCR was used to analyzed expression of PBX/Knotted 1 Homeobox 1 (pknox1) protein⁶. Immunohistochemistry staining, western blot, and RNA extraction were utilized to analyze the samples in both experience^6,7. Results. Macrophage-depletion BMMSCs and saline groups exhibited slower wound closure after 12-day assessment compared to macrophage presence MSCs groups (n=6). When injected systematically, MSCs homed to wound sites, and M2 polarization occurred at wound site, not at normal skin: RELM-α and CD68+ cells have higher percentage at wound sites treated with BMMSCs and JMMSCs than normal site and saline group (P<0.001). BMMSC and exosome treatments in mice had more cutaneous wound healing than BM/siRab27a infusion treatment after 12 days (P<0.05). Inhibiting miR-223 in exosomes reduces M2 macrophage polarization: CD206-positive macrophages in the miR-223 mimic group are higher than in the miR-223 inhibitor group (P<0.001)⁶. Gou et al. showed that Pknox1 mediated M2 macrophage polarization, and miR-223 bound and suppressed pknox1. Adding a mimic of miR-223 decreased concentration of pknox1 protein, and vice versa with inhibitor of miR-223. Pknox1 overexpression reduced M2 macrophage polarization compared to controlled miR-223+ group: amount of M2 macrophages markers such as Arginase-1, Fizz-1 are suppressed (P < 0.05) ⁷. Conclusions. Mesenchymal stem cells (MSCs) found to promote wound healing via immunomodulating effects through secreting exosome: increasing anti-inflammatory M2 phenotype and suppressing pro-inflammatory M1 phenotype. One mechanism is MiR-223/pknox1 axis that involves MSC-EVs-derived MiR-223^6,7. Thus, MSCs and MSC-EVs are potential novel therapeutic treatment in severe cutaneous burn wound.

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5. Wang Y, Han B, Wang Y, et al. Mesenchymal stem cell-secreted extracellular vesicles carrying TGF-β1 up-regulate miR-132 and promote mouse M2 macrophage polarization
6. He X, Dong Z, Cao Y, et al. MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing. Stem Cells Int. 2019;2019:7132708. doi:10.1155/2019/7132708
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