Adipose-Derived Stem Cell Extracellular Vesicles Improve Wound Closure and Angiogenesis in Diabetic Mice

Abstract

Background: Currently, there is a lack in therapy that promotes the reepithelialization of diabetic wounds as an alternative to skin grafting. Here, the authors hypothesized that extracellular vesicles from adipose-derived stem cells (ADSC-EVs) could accelerate wound closure through rescuing the function of keratinocytes in diabetic mice. Methods: The effect of ADSC-EVs on the biological function of human keratinocyte cells was assayed in vitro. In vivo, 81 male severe combined immune deficiency mice aged 8 weeks were divided randomly into the extracellular vesicle–treated diabetes group (n = 27), the phosphate-buffered saline–treated diabetes group (n = 27), and the phosphate-buffered saline–treated normal group (n = 27). A round, 8-mm-diameter, full-skin defect was performed on the back skin of each mouse. The wound closure kinetics, average healing time, reepithelialization rate, and neovascularization were evaluated by histological staining. Results: In vitro, ADSC-EVs improved proliferation, migration, and proangiogenic potential, and inhibited the apoptosis of human keratinocyte cells by suppressing Fasl expression with the optimal dose of 40 μg/mL. In vivo, postoperative dripping of ADSC-EVs at the dose of 40 μg/mL accelerated diabetic wound healing, with a 15.8% increase in closure rate and a 3.3-day decrease in average healing time. ADSC-EVs improved reepithelialization (18.2%) with enhanced epithelial proliferation and filaggrin expression, and suppressed epithelial apoptosis and Fasl expression. A 2.7-fold increase in the number of CD31-positive cells was also observed. Conclusion: ADSC-EVs improve diabetic wound closure and angiogenesis by enhancing keratinocyte-mediated reepithelialization and vascularization. Clinical Relevance Statement: ADSC-EVs could be developed as a regenerative medicine for diabetic wound care.

Stem Cell-Derived Extracellular Vesicles: Promising Therapeutic Opportunities for Diabetic Wound Healing

“…Wang et al discovered that ADSC-exos assisted in the recovery of diabetic wounds by suppressing the apoptosis and promoting re-epithelialization and angiogenesis of keratinocytes (KCs) conditioned with advanced glycation end-product (AGE) through inhibiting Fas/Fasl signaling pathway. 35 Similarly, Liu et al ADSC-EVs substantiated that exhibited capabilities in promoting HIF-1α mediated angiogenesis proliferation, migration, and tube formation of AGE-treated HUVECs. Specifically, the activation of hypoxia-related PI3K/AKT/mTOR signaling pathway induced HIF-1α and vascular endothelial growth factor (VEGF) upregulation to incorporate these promotion effects.…”

Exosomes from preconditioned mesenchymal stem cells: Tissue repair and regeneration

“…For instance, exosomes derived from ADSCs can be absorbed and internalized by human keratinocytes, thereby improving the diminished biological function of keratinocytes and enhancing their ability to proliferate, migrate, and facilitate neovascularization. Furthermore, pretreatments of MSCs can greatly enhance the therapeutic effect of their exosomes [ 71 ]. TAO et al.…”

Prospect of Mesenchymal Stem-Cell-Conditioned Medium in the Treatment of Acute Pancreatitis: A Systematic Review

“…These structural changes result in pancreatic endocrine and exocrine dysfunction. However, exosomes have shown the capacity to stimulate cell proliferation and induce cell activation, raising speculation that they may serve as a theoretical basis for the treatment of pancreatic diseases characterized by inflammation and structural damage [ 26 , 27 ].…”