Novel lipid mediator 7,14-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss.

Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7,14-dihydroxy-4,8,10,12,16,19-docosahexaenoic acid (7,14-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7,14-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic mice. MSCs treated with 7,14-diHDHA were delivered into mice every 5 days for 35 days. Blood glucose levels in diabetic mice were lowered by 7,14-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7,14-diHDHA-treated MSCs increased insulin β-cell ratio and decreased glucogan α-cell ratio in islets, as well as reduced macrophages in pancreas. 7,14-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7,14-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7,14-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in mice. Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7,14-diHDHA-primed MSCs.