14S,21R-dihydroxydocosahexaenoic acid remedies impaired healing and mesenchymal stem cell functions in diabetic wounds.
Treatment of diabetes-impaired wound healing remains a major unresolved medical challenge. Here, we identified suppressed formation of a novel reparative lipid mediator 14S,21R-dihydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14S,21R-diHDHA) in cutaneous wounds of diabetic db/db mice. These results indicate that diabetes impedes the biosynthetic pathways of 14S,21R-diHDHA in skin wounds. Administration of exogenous 14S,21R-diHDHA to wounds in diabetic animals rescued healing and angiogenesis. When db/db mesenchymal stem cells (MSCs) were administered together with 14S,21R-diHDHA to wounds in diabetic animals, they coacted to accelerate wound re-epithelialization, granulation tissue formation, and synergistically improved vascularization. In the pivotal cellular processes of angiogenesis, 14S,21R-diHDHA enhanced VEGF release, vasculature formation, and migration of db/db dermal microvascular endothelial cells (DMVECs), as well as remedied paracrine angiogenic functions of db/db MSCs, including VEGF secretion and the promotion of DMVEC migration and vasculature formation. Our results show that 14S,21R-diHDHA activates the p38 MAPK pathway in wounds, db/db MSCs, and DMVECs. Overall, the impeded formation of 14S,21R-diHDHA described in this study suggests that diabetes could affect the generation of pro-healing lipid mediators in wound healing. By restoring wound healing and MSC functions, 14S,21R-diHDHA is a new lead for the development of better therapeutics used in treating wounds of diabetics.
Center of Neuroscience Excellence, Louisiana State University Health Science Center, New Orleans, Louisiana 70112, USA.
Haibin
H
Tian
Yan
Y
Lu
Shraddha P
SP
Shah
Song
S
Hong
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D048909:Diabetes Complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000235:genetics; D014947:Wounds and Injuries / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D004281:Docosahexaenoic Acids; D048051:p38 Mitogen-Activated Protein Kinases