Journal
JOURNAL OF NANOBIOTECHNOLOGY
Volume 20, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12951-022-01656-7
Keywords
Extracellular vesicles; Exosomes; Wound healing; Diabetes; Serpin; Extracellular matrix
Funding
- National Institutes of Health [1R01-GM140137]
- Korea Health Technology R&D Project of the Korea Health Industry Development Institute (KHIDI) [HI19C1334]
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Chronic metabolic diseases such as diabetes is associated with delayed wound healing and dysregulated inflammatory phase of wound repair. This study focuses on the changes in extracellular vesicles (EVs) payload that mediates communication between immune cells and stromal cells in the wound bed, which regulate the rate of wound closure. By transferring EVs from genetically defined mouse models, the functional and molecular basis for differences in the pro-reparative biological activity of diabetic (db/db) vs. wildtype EVs in wound healing is demonstrated. This study establishes a novel therapeutic approach by engineering the payload of EVs, aiming to rescue the Serpin deficiency identified by proteomics and promote wound healing in db/db mice.
Chronic metabolic diseases such as diabetes are characterized by delayed wound healing and a dysregulation of the inflammatory phase of wound repair. Our study focuses on changes in the payload of extracellular vesicles (EVs) communicating between immune cells and stromal cells in the wound bed, which regulate the rate of wound closure. Adoptive transfer of EVs from genetically defined mouse models are used here to demonstrate a functional and molecular basis for differences in the pro-reparative biological activity of diabetic (db/db) vs. wildtype EVs in wound healing. We identify several members of the Serpin family of serine protease inhibitors that are absent in db/db EVs, then we overexpress Serpin A1, F2 and G1 in EVs to evaluate their effect on wound healing in db/db mice. Serpins have an important role in regulating levels of elastase, plasmin and complement factors that coordinate immune cell signaling in full thickness wounds in a diabetic model. Here, we establish a novel therapeutic approach by engineering the payload of EVs based on proteomic analysis. Serpin-loaded EVs were used to rescue the Serpin deficiency identified by proteomics and promote wound healing in db/db mice, as well as evaluated how EVs affected extracellular matrix remodeling and the resolution of tissue injury. Therefore, we propose that the identification of EV payloads that are downregulated in diabetic wounds can be systematically analyzed for their functional activity and potential as a therapeutic, based on whether their re-expression in engineered EVs restores normal kinetics of tissue repair in chronic wounds.
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