Fibroblast-Derived Extracellular Vesicle-Packaged Long Noncoding RNA Upregulated in Diabetic Skin Enhances Keratinocyte MMP-9 Expression and Delays Diabetic Wound Healing

Accurate communication between fibroblasts and keratinocytes is crucial for diabetic wound healing. Extracellular vesicles are being explored as essential mediators of intercellular commu-nication in the skin. However, the mechanisms underlying wound healing mediated by fibroblast -derived extracellular vesicles (Fib-EVs) remain unclear. The present study evaluated the role of long noncoding RNA upregulated in diabetic skin (lnc-URIDS) packed in Fib-EVs in the wound healing of streptozotocin-induced diabetes and the potential mechanisms of the effects. We demonstrated that high glucose induced the enrichment of lnc-URIDS in Fib-EVs, facilitated the transfer of lnc-URIDS to primary rat epidermal keratinocytes, and increased the expression of matrix metalloproteinase-9. Mechanistically, the binding of lnc-URIDS to YTH domain family protein-2 enhanced the degradation of YTH domain family protein-2 in the lysosomes, which increased the translational activity of the messenger RNA of matrix metalloproteinase-9 and ul-timately induced the degradation of collagen for wound healing. The results provided an insight into the crosstalk and cooperation between fibroblasts and keratinocytes in collagen homeostasis in diabetic wounds and clarified the mechanism by which lnc-URIDS degrades collagen for diabetic wound healing.(c) 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.

Automated summary

The enrichment of long noncoding RNA upregulated in diabetic skin (lnc-URIDS) in fibroblast-derived extracellular vesicles (Fib-EVs) was induced by high glucose, facilitating the transfer of lnc-URIDS to primary rat epidermal keratinocytes and increasing the expression of matrix metalloproteinase-9. Mechanistically, lnc-URIDS binding to YTH domain family protein-2 enhanced its degradation in the lysosomes, resulting in increased translational activity of matrix metalloproteinase-9 mRNA and ultimately leading to collagen degradation for diabetic wound healing.