Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Accelerate Diabetic Wound Healing via Promoting M2 Macrophage Polarization, Angiogenesis, and Collagen Deposition

Abstract

Some scholars have suggested that the clinical application of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) might represent a novel strategy to improve diabetic wound healing. However, the mechanisms underlying the effects of hucMSCs-exo on wound healing remain poorly understood. This study aimed to identify the mechanism of hucMSCs-exo in treating diabetic wounds. HucMSCs-exo were isolated from human umbilical cord mesenchymal stem cells (hucMSCs) and subcutaneously injected into full-thickness wounds in diabetic rats. Wound healing closure rates and histological analysis were performed. The levels of tumor necrosis factor-α (TNF-α), macrophage mannose receptor (MMR/CD206), platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), and vascular endothelial growth factor (VEGF) were detected by immunohistochemistry. The degree of collagen deposition was examined using Masson’s trichrome staining. Gross evaluation of wound healing was carried out from day 0 to 14 post-surgery, and the wound site was harvested for histology on days 3, 7, and 14 post-wounding. HucMSCs-exo transplantation increased diabetic wound healing. In vitro, hucMSCs-exo promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and NIH-3T3 cells. In vivo, hucMSCs-exo reduced wound area and inflammatory infiltration and increased collagen fibers. In addition, wound tissues in the hucMSCs-exo group had higher CD206, CD31, and VEGF expressions and lower TNF-α levels than those in the control group on day 14. Our results demonstrated that hucMSCs-exo facilitated diabetic wound repair by inducing anti-inflammatory macrophages and promoting angiogenesis and collagen deposition.

Human umbilical cord mesenchymal stem cell-derived exosomes promote murine skin wound healing by neutrophil and macrophage modulations revealed by single-cell RNA sequencing

“…In addition, upregulated TLR4 is believed to be involved in hucMSC-derived exosome-induced M2 macrophage inflammation and repair (74). Similar to reported hucMSC-Exosomes' effect on liver, we also detected the elevation of ERK pathway in neutrophils, its promotion of cell survival may be the cause of increase neutrophils (75).However, it is important to note that hucMSC-Exosomes consist of hundreds of proteins, RNAs, and miRNAs, which collectively result in multifaceted effects from complex combinations of multiple molecules (7,49,65,(76)(77)(78). Therefore, it is improbable that a single bioactive molecule in vivo could replicate the effects of hucMSC-Exosomes in the microenvironments of wounds.…”

“…Exosomes, the main effector of MSCs paracrine production, are thought to have more stable biological effects, higher transduction efficiency, and easier quantification and storage ( 5 ). Studies have shown that human umbilical cord mesenchymal stem cells derived exosomes (hucMSC-Exosomes) can promote wound regeneration and repair by improving immune regulation, stimulating angiogenesis, promoting keratinocyte proliferation, and mediating extracellular matrix remodeling ( 6 , 7 ). Although evidence exists regarding the promotion of wound healing by hucMSC-Exosomes, the molecular mechanisms underlying the actions of different cell populations and the interactions between cells have not been consistent in reports ( 7 – 9 ).…”

Human umbilical cord mesenchymal stem cells derived extracellular vesicles alleviate salpingitis by promoting M1–to–M2 transformation

“…Some studies have confirmed that MSCs can promote the transformation of M1 macrophages to the M2 type through the paracrine pathway ( Xin et al, 2020 ; Li et al, 2022 ; Teng et al, 2022 ; Zhang et al, 2022 ), suggesting that M2-type macrophages are important in the MSC-mediated treatment of salpingitis. Based on previous studies, we used CT intravaginal inoculation to generate a mouse model of salpingitis.…”

Extracellular Vesicle-Based Hydrogels for Wound Healing Applications

“…All these studies have achieved a synergic association between EVs and hydrogels in terms of their functional and wound-healing properties [ 70 , 71 , 72 , 73 ]. However, as mentioned before, EV conservation requires improvement before reaching the clinics.…”