Therapeutic Potential of Exosomes Derived from Diabetic Adipose Stem Cells in Cutaneous Wound Healing of db/db Mice

Abstract

(1) Background: Diabetes impairs angiogenesis and wound healing. Paracrine secretion from adipose stem cells (ASCs) contains membrane-bound nano-vesicles called exosomes (ASC-Exo) but the functional role and therapeutic potential of diabetic ASC-Exo in wound healing are unknown. This study aims to investigate the in vivo mechanistic basis by which diabetic ASC-Exo enhance cutaneous wound healing in a diabetic mouse model. (2) Methods: Topically applied exosomes could efficiently target and preferentially accumulate in wound tissue, and the cellular origin, ASC or dermal fibroblast (DFb), has no influence on the biodistribution pattern of exosomes. In vivo, full-thickness wounds in diabetic mice were treated either with ASC-Exo, DFb-Exo, or phosphate-buffered saline (PBS) topically. ASC-Exo stimulated wound healing by dermal cell proliferation, keratinocyte proliferation, and angiogenesis compared with DFb-Exo and PBS-treated wounds. (3) Results: Diabetic ASC-Exo stimulated resident monocytes/macrophages to secrete more TGF-β1 and activate the TGF-β/Smad3 signaling pathway. Fibroblasts activated by TGF-β1containing exosomes from ASCs initiate the production of TGF-β1 protein in an autocrine fashion, which leads to more proliferation and activation of fibroblasts. TGF-β1 is centrally involved in diabetic ASC-Exo mediated cellular crosstalk as an important early response to initiating wound regeneration. (4) Conclusions: The application of diabetic ASC-Exo informs the potential utility of a cell-free therapy in diabetic wound healing.

Effect of mesenchymal stromal cells‐derived extracellular vesicles as a treatment to heal diabetic wounds: A meta‐analysis

“…From a total of 2975 linked investigation that was inspected, 29 articles published between 2016 and 2022 fit the inclusion criteria and were selected and involved in the study 26‐53 . Table 2 offerings the verdicts from these studies.…”

“…In the studies nominated for the meta‐analysis, 381 animals with diabetes mellitus were in the picked studies' baseline, 217 of them were using MSC‐EVs, and 173 were using control 26‐53 . MSCs‐EVs had a significantly higher rate of wound closure of DWs, lower width of the scar, higher collagen deposition, and higher rate of re‐epithelialisation compared with the control.…”

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

“…Besides, TGF-β1 could activate the FBs in an autocrine manner to increase TGF-β1 production, thus promoting ECM deposition and re-epithelization leading to the healing of diabetic wounds. 34 …”

Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing

“…The in-depth investigation confirmed that ADSC-exos could facilitate diabetic wound healing by modulating SIRT3/SOD2 to improve high-glucose-induced oxidative stress levels, promote angiogenesis, and reduce mitochondrial functional impairment and the inflammatory response. In full-thickness wounds in diabetic mice, ADSC-exos separated from diabetic mice could promote healing by enhancing dermal cell proliferation, keratinocyte (KC) proliferation, and angiogenesis [ 27 ]. Moreover, these ADSC-exos stimulated monocytes/macrophages to produce large amounts of TGF-β1 and activated the TGF-β/Smad3 pathway to stimulate fibroblast proliferation and activation.…”