Exosomes Derived from Human Endothelial Progenitor Cells Accelerate Cutaneous Wound Healing by Promoting Angiogenesis Through Erk1/2 Signaling

Abstract

Chronic skin wounds represent one of the most common and disabling complications of diabetes. Endothelial progenitor cells (EPCs) are precursors of endothelial cells and can enhance diabetic wound repair by facilitating neovascularization. Recent studies indicate that the transplanted cells exert therapeutic effects primarily via a paracrine mechanism and exosomes are an important paracrine factor that can be directly used as therapeutic agents for regenerative medicine. However, application of exosomes in diabetic wound repair has been rarely reported. In this study, we demonstrated that the exosomes derived from human umbilical cord blood-derived EPCs (EPC-Exos) possessed robust pro-angiogenic and wound healing effects in streptozotocin-induced diabetic rats. By using a series of in vitro functional assays, we found that EPC-Exos could be incorporated into endothelial cells and significantly enhance endothelial cells' proliferation, migration, and angiogenic tubule formation. Moreover, microarray analyses indicated that exosomes treatment markedly altered the expression of a class of genes involved in Erk1/2 signaling pathway. It was further confirmed with functional study that this signaling process was the critical mediator during the exosomes-induced angiogenic responses of endothelial cells. Therefore, EPC-Exos are able to stimulate angiogenic activities of endothelial cells by activating Erk1/2 signaling, which finally facilitates cutaneous wound repair and regeneration.

Hydrogen Sulfide-Preconditioning of Human Endothelial Progenitor Cells Transplantation Improves Re-Endothelialization in Nude Mice with Carotid Artery Injury

“…The expressions of endothelial markers of cultured EPCs were examined using flow cytometry analysis with the following antibodies: phycoerythrin (PE)-labeled monoclonal mouse anti-human antibodies recognizing CD31 (BD Pharmingen), von Willebrand factor (vWF) (BD Pharmingen), kinase-insert domain receptor (KDR) (R&D Systems), and CD14 (BD Pharmingen). Based on the flow cytometry findings, the adherent mononuclear cells were identified as early EPCs which were consistent with previous reports [24, 25]. …”

Association of Extracellular Membrane Vesicles with Cutaneous Wound Healing

“…Additionally, the downstream target of the Erk1/2 signalling pathway such as inhibitor of DNA binding 1, cyclooxygenase 1, VEGFA, VEGFR-2, c-Myc and cyclin-D1, were also increased after treatment with exosomes [106,122,123]. This provides further evidence that exosomes enhance endothelial cell function through activation of the Erk1/2 signalling pathway (Figure 7) [106].…”

Roxadustat promotes angiogenesis through HIF‐1α/VEGF/VEGFR2 signaling and accelerates cutaneous wound healing in diabetic rats

“…For evaluation of angiogenesis in the defect areas, three rats in each group were perfused with Microfil (Flowtech, Carver, MA) at day 14 after surgery according to previously published articles . Briefly, after anesthesia, the rib cage of the rats was opened.…”