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. 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 assays^6,7. 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.

1. Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S. Burn
2. Nat Rev Dis Primers. Feb 13 2020;6(1):11.
3. Magne B, Lataillade JJ, Trouillas Mesenchymal Stromal Cell Preconditioning: The Next Step Toward a Customized Treatment For Severe Burn. Stem Cells Dev. Oct 15 2018;27(20):1385-1405.
4. Martin KE, García AJ. Macrophage phenotypes in tissue repair and the foreign body response: Implications for biomaterial-based regenerative medicine Acta Biomater. Mar 26 2021.
5. Abo-Elkheir W, Hamza F, Elmofty AM, et al. Role of cord blood and bone marrow mesenchymal stem cells in recent deep burn: a case-control prospective Am J Stem Cells. 2017;6(3):23-35.
6. 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
7. 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.
8. Gou W, Zhang Z, Yang C, Li MiR-223/Pknox1 axis protects mice from CVB3-induced viral myocarditis by modulating macrophage polarization. Exp Cell Res. May 1 2018;366(1):41-48.