Introduction and Objective: Mesenchymal stem cells (MSCs) from infants born to mothers with obesity and diabetes demonstrate increased adipogenic capacity, but the molecular mechanisms underlying this effect are unclear. The objective was to quantify changes in miRNA abundance in MSCs resulting from diabetes exposure and map their potential downstream pathways.Methods: Pregnant persons, 18 control and 17 with diabetes, either GDM or T2D, presenting for elective caesarian section at term were recruited. The diagnosis of GDM or T2D was based on prevailing criteria. Type 1 diabetes, preeclampsia, or chronic hypertension were exclusions. MSCs were isolated from umbilical cord Wharton’s jelly using the “explant culture” method. RNA was extracted using miRNeasy kit. nCounter Human v3 miRNA Panel (NanoString Technologies) was used for miRNA profiling. Raw gene counts were normalized by log2 counts-per-million. Transformed data were fit to linear models using generalized least squares, and a moderated t-statistic was computed using empirical Bayes methods. Results were considered significant if log2 fold change ± 0.5 and p-value < 0.05 after controlling for birthweight, gestational age, maternal age, and pre-pregnancy BMI. Pathway analysis utilized mRNA targets of the miRNAs (validated in 2 databases) with an adjusted p-value < 0.05.Results: miR-548e-3p, miR-579-3p, and miR-1180-3p demonstrated lower abundance in the MSCs exposed to maternal diabetes (fold change -1.76, -0.74 and -0.55; p-value 0.020, 0.032, and 0.017, respectively). GO analysis showed enrichment of histone modification and programmed cell death (apoptotic) signaling pathways (24-34-fold enrichment, p<0.03). From Reactome analysis, BMAL1:CLOCK activation and cholesterol biosynthesis pathways were enriched (15-44-fold enrichment, p<0.05).Conclusion: Specific differences in miRNA abundance, leading to circadian rhythm and epigenetic modifications, may be mechanisms underlying increased adipogenesis thereby placing offspring at risk for obesity and future metabolic disease.
W. Lee: None. M. Onopiuk: None. B. Nelson: None. J. Friedman: None. S.J. Borengasser: None. J. Tryggestad: Research Support; Current; Abbott Diabetes. Other – Site PI for study; Current; Ascendis Pharma A/S, Lilly Diabetes.
Harold Hamm Diabetes Center Team Science Grant
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