Extracellular Vesicles Derived from Adipose-Derived Stem Cells Accelerate Diabetic Wound Healing by Suppressing the Expression of Matrix Metalloproteinase-9

Abstract

Background: The healing of diabetic wounds is poor due to a collagen deposition disorder. Matrix metalloproteinase-9 (MMP-9) is closely related to collagen deposition in the process of tissue repair. Many studies have demonstrated that extracellular vesicles derived from adipose-derived stem cells (ADSC-EVs) promote diabetic wound healing by enhancing collagen deposition. Objective: In this study, we explored if ADSC-EVs could downregulate the expression of MMP-9 in diabetic wounds and promote wound healing by improving collagen deposition. The potential effects of ADSC-EVs on MMP-9 and diabetic wound healing were tested both in vitro and in vivo. Methods: We first evaluated the effect of ADSC-EVs on the proliferation and MMP-9 secretion of HaCaT cells treated with advanced glycation end product-bovine serum albumin (AGE-BSA), using CCK-8 western blot and MMP-9 enzyme-linked immunosorbent assay(ELISA). Next, the effect of ADSC-EVs on the healing, re-epithelialisation, collagen deposition, and MMP-9 concentration in diabetic wound fluids was evaluated in an immunodeficient mouse model via MMP-9 ELISA and haematoxylin and eosin, Masson’s trichrome, and immunofluorescence staining for MMP-9. Results: In vitro, ADSC-EVs promoted the proliferation and MMP-9 secretion of HaCaT cells.In vivo, ADSC-EVs accelerated diabetic wound healing by improving re-epithelialisation and collagen deposition and by inhibiting the expression of MMP-9. Conclusion: ADSC-EVs possessed the healing of diabetic wounds in a mouse model by inhibiting downregulating MMP-9 and improving collagen deposition.Thus ,ADSC-EVs are a promising candidate for the treatment of diabetic wounds .

Targeting matrix metalloproteases in diabetic wound healing

“…In vitro studies demonstrated that ADSC-EVs promotes the proliferation of AGEs-BSA-treated HaCaT cells, while inhibits the secretion of MMP-9. Besides, ADSC-EVs improves the wound healing rate of diabetic mice through accelerating the re-epithelialisation, facilitating COL deposition, and reducing MMP-9 levels in the wound fluids (32).…”

Sodium alginate/gelatin hydrogels loaded with adipose‐derived mesenchymal stem cells promote wound healing in diabetic rats

“…ASCs promote granulation tissue formation and facilitate diabetic wound healing 24 . Furthermore, ASCs have been shown to improve wound healing through promoting collagen synthesis 25,26 . To our knowledge, the effects of Gel‐Al hydrogels and ASC complexes in diabetic wound healing have not been elucidated.…”

“…24 Furthermore, ASCs have been shown to improve wound healing through promoting collagen synthesis. 25,26 To our knowledge, the effects of Gel-Al hydrogels and ASC complexes in diabetic wound healing have not been elucidated. In this study, we selected ASCs in combination with Gel-Al hydrogel for the treatment of chronic diabetic wound.…”

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

“…In vivo animal model, ADSC-EVs accelerated epithelization and collagen enrichment to promote diabetic wound closure by inhibiting MMP-9 expression. 31 Xiao et al demonstrated that in vitro, ADSC-exos increased the proliferative and migratory abilities of HDFs and promoted proliferation and tube formation in HUVECs. Additionally, these researchers combined ADSC-exos with human acellular amniotic membrane (hAAM) biomaterials, and hAAM exhibited favorable efficacy when combined with ADSC-exos.…”