AUTHOR=Lu Yan , Tian Haibin , Peng Hongying , Wang Quansheng , Bunnell Bruce A. , Bazan Nicolas G. , Hong Song 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=12

YEAR=2024

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2024.1380059

DOI=10.3389/fcell.2024.1380059

ISSN=2296-634X

ABSTRACT=<p><bold>Introduction:</bold> 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<italic>S</italic>,14<italic>R</italic>-dihydroxy-4<italic>Z</italic>,8<italic>E</italic>,10<italic>Z</italic>,12<italic>E</italic>,16<italic>Z</italic>,19<italic>Z</italic>-docosahexaenoic acid (7<italic>S</italic>,14<italic>R</italic>-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7<italic>S</italic>,14<italic>R</italic>-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic <italic>db/db</italic> mice.</p><p><bold>Methods:</bold> MSCs treated with 7<italic>S</italic>,14<italic>R</italic>-diHDHA were delivered into <italic>db/db</italic> mice <italic>i.v.</italic> every 5 days for 35 days.</p><p><bold>Results:</bold> Blood glucose levels in diabetic mice were lowered by 7<italic>S</italic>,14<italic>R</italic>-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7<italic>S</italic>,14<italic>R</italic>-diHDHA-treated MSCs increased insulin<sup>+</sup> β-cell ratio and decreased glucogan<sup>+</sup> α-cell ratio in islets, as well as reduced macrophages in pancreas. 7<italic>S</italic>,14<italic>R</italic>-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7<italic>S</italic>,14<italic>R</italic>-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7<italic>S</italic>,14<italic>R</italic>-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in <italic>db/db</italic> mice.</p><p><bold>Discussion:</bold> Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7<italic>S</italic>,14<italic>R</italic>-diHDHA-primed MSCs.</p>